Metab Ca - P
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Calcium Metabolism
andHypocalcemia
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Calcium metabolism
99% of total body calcium in the bone .
1% in ICF ,ECF ,& cell membranes .
Calcium weight is 400mg/kg in infant &
950mg/kg in adult .
The 1% can be divided in 3 components :
1) 50% ionized . 2) 40% bound to protein .3)10% complex w/anions{citrate,phosphate,..
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Calcium metabolism
physiologic functions :
1.blood coagulation .
2.muscle contraction .3.neuromuscular transmission .
4.Skeletal growth & mineralization
Ionized Ca is physiologically important .
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Three Forms of Circulating Ca2+
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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
Neuron excitation
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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....)
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Calcium metabolism
Serum CA level is determined by net
absorption (GI) & excretion (RENAL).
Each components is tightly regulated-hormonally- to keep normal serum level .
Total CA is usually measured & provides
satisfactory assessment of ionized form .
However we have exceptions:
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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 thebloodstream.
There is constant exchange of calcium between bone and blood.
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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.
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Calcium metaolism
However we have exceptions: Decreased serum albumin .
Each 1 g/dl of serum albumin binds about 0.8
mg/dl of calcium .Cac=Cam+{0.8* decrease in serum albumin .} Acid base disturbance .
( Affect binding to protein .)Increase when PH increased .
Decrease when PH decreased .
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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 verynarrow range.
This is achieved by an elaborate system of
controls
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Control of cellular Ca homeostasis is as carefullymaintained 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 shiftit away from cytosolic pools.
Regulation of Intracellular [Calcium]
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Three definable fractions of calcium in
serum: Ionized calcium 50%
Protein-bound calcium 40% 90% bound to albumin
Remainder bound to globulins
Calcium complexed to serum constituents 10% Citrate and phosphate
Extracellular Calcium
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Binding of calcium to albumin is pH dependent
Acute alkalosis increases calcium binding to
protein and decreases ionized calcium
Patients who develop acute respiratory alkalosishave increased neural excitability and are prone to
seizures due to low ionized calcium in the
extracellular fluid which results in increased
permeability to sodium ions
Extracellular Calcium
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Calcium and the Cell
Translocation across the plasma membrane Translocation across the ER and mitochondrion;
Ca2+ ATPase in ER and plasma membrane
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Calcium Turnover
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Calcium homeostasis
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PTH,
Calcium &
Phosphate
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Calcium in Blood and Bone
Ca2+ normally ranges from 8.5-10 mg/dLin the plasma.
The active free ionized Ca2+ is only about
48% 46% is bound to protein in a non-diffusible state while 6% is complexed tosalt.
Only free, ionized Ca2+ is biologicallyactive.
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Phosphate Turnover
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Phosphorous in Blood and Bone
PO4 normal plasma concentration is 3.0-
4.5 mg/dL. 87% is diffusible, with 35%
complexed to different ions and 52%
ionized.
13% is in a non-diffusible protein bound
state. 85-90% is found in bone.
The rest is in ATP, cAMP, and proteins
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Osteoclasts and Ca2+
Resorption
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Hormonal
Control ofBones
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Hormonal Control of Ca2+
Three principal hormones regulate Ca2+ and three
organs that function in Ca2+ homeostasis.
Parathyroid hormone (PTH), 1,25-dihydroxy
Vitamin D3 (Vitamin D3), and Calcitonin,regulate Ca2+ resorption, reabsorption, absorption
and excretion from the bone, kidney and intestine.
In addition, many other hormones effect bone
formation and resorption.
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Calcium and the Skeleton
A, absorption is stimulated by Vit D; S, secretion GF, glomerular filtration; TR, tubular reabsorption
of Ca2+ is stimulated by PTH
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PTH and Osteoblastogenesis
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Osteoclast Mediated Bone Resorption
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PTH and
Kidney
PTH acts on the
distal tubule
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Calcium metabolism
Calcium regulation :mainly by 3 commonhormones :
1}Parathyroid hormone .
2}Vitamin D .
3}Calcitonin .
Calcium metabolism
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Calcium metabolism
Vitamin D Vitamin D :provide Ca & PO4 to ECF for bone
mineralization . Deficiency in children..Rickets Deficiency in adult..Osteomalacia 7-dehydrocholestrol(skin)cholecalciferol
25-OH- cholecalciferol(liver)1- 25-OH-cholecalciferol(kidney) MOA: steroid so enter nucleus & bind receptor that leads
to expose part of DNAmRNACalbindin-D protein inepithlium of intestine,kidney,..that do the action .
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Vitamin D3 synthesis occurs in keratinocytes in theskin.
7-dehydrocholesterol is photoconverted toprevitamin D3, then spontaneously converts tovitamin D3.
Previtamin D3 will become degraded by overexposure to UV light and thus is not overproduced.
Also 1,25-dihydroxy-D (the end product of vitaminD synthesis) feeds back to inhibit its production.
Synthesis of Vitamin D
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PTH stimulates vitamin D synthesis. In the winteror if exposure to sunlight is limited (indoor jobs!),then dietary vitamin D is essential.
Vitamin D itself is inactive, it requires modificationto the active metabolite, 1,25-dihydroxy-D.
The first hydroxylation reaction takes place in theliver yielding 25-hydroxy D.
Then 25-hydroxy D is transported to the kidneywhere the second hydroxylation reaction takesplace.
Synthesis of Vitamin D
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The mitochondrial P450 enzyme 1-hydroxylaseconverts it to 1,25-dihydroxy-D, the most potentmetabolite of Vitamin D.
The 1
-hydroxylase enzyme is the point ofregulation of D synthesis. Feedback regulation by 1,25-dihydroxy D inhibits
this enzyme.
PTH stimulates 1-hydroxylase and increases1,25-dihydroxy D.
Synthesis of Vitamin D
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25-OH-D3 is also hydroxylated in the 24 position
which inactivates it.
If excess 1,25-(OH)2-D is produced, it can also by
24-hydroxylated to remove it. Phosphate inhibits 1-hydroxylase and decreased
levels of PO4 stimulate 1-hydroxylase activity
Synthesis of Vitamin D
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Calcium metabolism
Vitamin D Actions:
1)increase Ca absorption from intestine.
2) increase PO4 absorption from intestine.3) increase renal reabsorption of Ca &PO4.
4) increase bone resorption from old bone
&mineralize new bone{net resorption} .Overall effect :increase serum Ca & PO4 .
Vit i D M t b li
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Vitamin D Metabolism
Transport and Metabolic Sequence of
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Transport and Metabolic Sequence ofActivation of Vitamin D
Proposed Mechanism of Action of
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Proposed Mechanism of Action of
1,25-DihydroxyD3 in Intestine
l i b li
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Calcium metabolism
Vitamin D Regulation :
Ca..-ve PTH . PO4.-ve VIT D . VIT D..-ve PTH . VIT D.-ve 25OHD . PTH +ve VIT .
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Regulation of Vitamin D Metabolism
PTH increases 1-hydroxylase activity, increasing
production of active form.
This increases calcium absorption from the intestines,
increases calcium release from bone, and decreases loss of
calcium through the kidney.
As a result, PTH secretion decreases, decreasing 1-
hydroxylase activity (negative feedback).
Low phosphate concentrations also increase 1-hydroxylase
activity (vitamin D increases phosphate reabsorption from
the urine).
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Vitamin D promotes intestinal
calcium absorption
Vitamin D acts via steroid hormone like
receptor to increase transcriptional and
translational activity
One gene product is calcium-binding
protein (CaBP)
CaBP facilitates calcium uptake by
intestinal cells
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Clinical correlate
Vitamin D-dependent rickets type II
Mutation in 1,25-(OH)2-D receptor
Disorder characterized by impairedintestinal calcium absorption
Results in rickets or osteomalacia despite
increased levels of 1,25-(OH)2-D in
circulation
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Vitamin D Deficiency: Rickets Inadequate intake and absence of sunlight
The most prominent clinical effect of Vitamin D
deficiency is osteomalacia, or the defective
mineralization of the bone matrix
Osteoblasts contain the vitamin D receptor Vitamin D deficiency in children produces rickets
A deficiency of renal 1-hydroxylase produces
vitamin D-resistant rickets Sex linked gene on the X chromosome
Renal tubular defect of phosphate resorption
Teeth may be hypoplastic and eruption may be retarded
C l i b li
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Calcium metabolism
PTH hormone Major hormone in regulation serum Ca .]
Synthesis & secreted from chief cells of
parathyroid gland .
MOA :
polypeptide that binds to specific receptors
{G proteins} that lead to increase 2nd
messenger cAMP that leads to physiologic
actions of the hormone .
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Parathyroid Glands
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Parathyroid Hormone Structure Synthesized in
the 4 para-thyroid glands
PreProPTH 115 aa precursor
giving a 90 aaprohormone Cleaved at -6/-7
84 residues in
the maturepeptide Regulator of
Ca2+
homeostasis
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Parathyroid Hormone Biosynthesis
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Regulation of PTH
The dominant regulator of PTH is plasmaCa2+.
Secretion of PTH is inversely related to
[Ca2+]. Maximum secretion of PTH occurs at
plasma Ca2+ below 3.5 mg/dL.
At Ca2+ above 5.5 mg/dL, PTH secretion ismaximally inhibited.
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Calcium Sensing
Receptor (CaSR)
Parathyroid chief cells contain a Ca2+ sensing receptor (CaSR)
7 transmembrane segments (We will see a lot of 7 TM receptors)
mM affinity for Ca2+
GPCR of the GPLC and GI varieties Generates inositol 1,4, 5-trisphosphate which increases
intracellular Ca2+
There are two paradoxes
The receptor responds to decreasing concentrations of agonist
Low extracellular Ca2+ increases intracellular Ca2+
Also found in thyroid C cells (calcitonin), kidney, and brain
Circulating Forms of PTH
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Circulating Forms of PTH
Intact, active PTH of 84 aa
Inactive carboxyterminal fragments lack the 1-34 activedomain
PTH t1/2 (half life) is 2-3 min Liver (2/3rds) and kidney (1/3rd) are major sites of
fragmentation
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PTH secretion responds to small alterations inplasma Ca2+ within seconds.
A unique calcium receptor within the parathyroidcell plasma membrane senses changes in theextracellular fluid concentration of Ca2+.
This is a typical G-protein coupled receptor thatactivates phospholipase C and inhibits adenylatecyclaseresult is increase in intracellular Ca2+via generation of inositol phosphates and decreasein cAMP which prevents exocytosis of PTH fromsecretory granules.
Regulation of PTH
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Calcium
regulates
PTHsecretion
P h id H R
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Parathyroid Hormone Receptor 7 TM
GPCR
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PTH
Biosynthesis PTH is co-secreted
with chromogranin
A, a protein;significance
unknown
Calcium metabolism
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Calcium metabolism
PTH hormone Actions : 1)increase bone resorption..increase Ca & PO4 in
serum .
2)increase renal Ca reabsorption . 3)increase Ca absorption from intestine indirectlyby increase VITD .
4)decrease PO4 reabsorption from proximal
tubules increase ionized Ca . Overall effect :increase serum Ca & decrease
serumPO4 .
Calcium metabolism
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Calcium metabolism
PTH hormone Regulation: Ca senor proteins that increase PTH when
Ca level decreased & decrease PTH when
Ca level increased . PTH increase VIT D level by activation
1-Ohlase .
Increase PO4 leads to increase PTH(bydecreasing Ca level ) . Mg decrease leads to deacrease PTH level .
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Mechanism of Action of PTH
PTH binds to a G protein-coupled receptor. Binding of PTH to its receptor activates 2 signaling
pathways:
- increased cyclic AMP
- increased phospholipase C Activation of PKA appears to be sufficient to decrease
bone mineralization Both PKA and PKC activity appear to be required for
increased resorption of calcium by the kidneys
Regulation of PTH Secretion
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Regulation of PTH Secretion
PTH is released in response to changes in plasma calcium levels.
- Low calcium results in high PTH release.
- High calcium results in low PTH release. PTH cells contain a receptor for calcium, coupled to a G protein. Result of calcium binding: increased phospholipase C, decreased
cyclic AMP. Low calcium results in higher cAMP, PTH release.
Also, vitamin D inhibits PTH release (negative feedback).
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PTH-Related Peptide
Has high degree of homology to PTH, but is not fromthe same gene.
Can activate the PTH receptor. In certain cancer patients with high PTH-related
peptide levels, this peptide causes hypercalcemia. But, its normal physiological role is not clear.
- mammary gland development/lactation?
- kidney glomerular function?
- growth and development?
PTH P P th id R l t d P t i
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PTHrP; Parathyroid Related Protein
Calcium metabolism
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Calcium metabolism
Calcitonin Is synthesized & secreted by Para follicular cells of
thyroid . MOA :1) Peptide that inhibit bone osteoclast
& so inhibit bone resorption .
2)increase renal excetion . Increase secretion when Ca level increase . Action:decrease CA level .
Overall effect : decrease serum Ca .
Calcitonin
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Calcitonin
Product of
parafollicular C cellsof the thyroid
32 aa
Inhibits osteoclastmediated bone
resorption
This decreases serumCa2+
Promotes renal
excretion of Ca2+
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Calcitonin
Calcitonin acts to decrease plasma Ca2+ levels. While PTH and vitamin D act to increase plasma
Ca2+-- only calcitonin causes a decrease inplasma Ca2+.
Calcitonin is synthesized and secreted by theparafollicular cells of the thyroid gland.
They are distinct from thyroid follicular cells by
their large size, pale cytoplasm, and smallsecretory granules.
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The major stimulus of calcitonin secretion
is a rise in plasma Ca2+ levels
Calcitonin is a physiological antagonist to
PTH with regard to Ca2+ homeostasis
Calcitonin
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The target cell for calcitonin is theosteoclast.
Calcitonin acts via increased cAMP
concentrations to inhibit osteoclast motilityand cell shape and inactivates them.
The major effect of calcitoninadministration is a rapid fall in Ca2+ causedby inhibition of bone resorption.
Calcitonin
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Actions of Calcitonin
The major action of calcitonin is on bone metabolism. Calcitonin inhibits activity of osteoclasts, resulting in
decreased bone resorption (and decreased plasma Ca
levels).
calcitonin(-)
osteoclasts: destroy bone to
release Ca
Decreasedresorption
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Role of calcitonin in normal Ca2+ control is notunderstoodmay be more important in control of boneremodeling.
Used clinically in treatment of hypercalcelmia and in
certain bone diseases in which sustained reduction ofosteoclastic resorption is therapeutically advantageous. Chronic excess of calcitonin does not produce
hypocalcemia and removal of parafollicular cells does notcause hypercalcemia. PTH and Vitamin D3 regulation
dominate. May be more important in regulating bone remodeling
than in Ca2+ homeostasis.
Calcitonin
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What is the Role of Calcitonin in Humans?
Removal of the thyroid gland has no effect on plasma
Ca levels!
Excessive calcitonin release does not affect bone
metabolism! Other mechanisms are more important in regulating
calcium metabolism (i.e., PTH and vitamin D).
Calcitonin Gene-Related Peptide
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Calcitonin Gene-Related Peptide
(CGRP)
The calcitonin gene produces several products due to
alternative splicing of the RNA.
CGRP is an alternative product of the calcitonin gene.
CGRP does NOT bind to the calcitonin receptor. CGRP is expressed in thyroid, heart, lungs, GI tract,
and nervous tissue.
It is believed to function as a neurotransmitter, not as
a regulator of Ca.
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Oth F t I fl i B d C l i
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Other Factors Influencing Bone and Calcium
Metabolism
Estrogens and Androgens: both stimulate boneformation during childhood and puberty.
Estrogen inhibits PTH-stimulated bone resorption.
Estrogen increases calcitonin levels Osteoblasts have estrogen receptors, respond to
estrogen with bone growth. Postmenopausal women (low estrogen) have an
increased incidence of osteoporosis and bonefractures.
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Hypocalcemia
Causes of hypocalcemia Specific causes in neonates Early neonatal hypocalcemia:(within 48-72 hour of birth)
Causes: 1- prematurity: poor intake, decrease response to
Vit. D, increase calcitoni, decrease albumin. 2- birth asphyxia: delayed introduction to feed,
increase calcitonin, increased endogenous PO4 load,
alkali therapy.
3- infant of diabetic mother: functional
parahypothyroidism induced by Mg defficiency haspredominant role
Causes of Hypocalcemia
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Causes of HypocalcemiaHypoparathyroid Nonparathyroid PTH Resistance
Postoperative Vitamin Ddeficiency
Pseudo-hypoparathyroidism
Idiopathic MalabsorptionPost radiation Liver disease
Kidney disease
Vitamin Dresistance
Sequence of Adjustments to
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q jHypocalcemia
Specific causes in neonates (cont )
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Specific causes in neonates (cont.)
4- IUGR: interruption Ca delivery across
placenta, prematurity, asphyxia.
Serum Ca correlate directly to gestational age.
Specific causes in neonates (cont )
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Specific causes in neonates (cont.)
II. Late neonatal hypocalcemia: happen from 5
days of birth, may appear till 6 weeks of age. Causes:
1. Exogenous PO4 load, most common due to highPO4 content in formula, or cows milk and decreased
in GFR contribute also.
2. Mg deficiency.
3. Transient hypoparathyroidism4. Hypoparathyroidism due to other causes: (idiopathic,
congenital, maternal hyperparathyroidism,
hypomagnesemia)
Hypoparathyroidism:
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Hypoparathyroidism:
1. DiGeorge syndrome: aplasia or hypoplasia of
parathyroid gland.
associated with different anomalies includingcardiac and facial anomaly mainly and also VATER
and CHARGE associations.
3. X-linked hypoparathyroidism (absent of the gland
that affect boys and appeared with the first 6 months
of age.
4. AR hypoparathyroidism with dymorphic features:
mutation of parathyroid hormone gene.
4. HDR syndrome: AD consist from (nervedeafness, renal dysplasia, and hypoparathyroidism)
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5. Autoimmune polyglandular syndrome type I: AR, dueto mutation in autoimmune regulator gene
Consist from (hypoparathyroidism, addisson disease,
mucocutaneous candidiasis).
6. Calcium sensor receptor gene mutation.
7. Kearns-Sayre syndrome: mitochondrial inherited
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7. Kearns Sayre syndrome: mitochondrial inheriteddisorder. (ie, external ophthalmoplegia, ataxia,
sensorineural deafness, heart block, and elevated
cerebral spinal fluid [CSF] protein), are associated withhypoparathyroidism. Hypothyroidism affect after age of
5 years
8. Hemochromatosis: iron overload
9. Wilson disease: copper overload
10. Postsurgical and irradiational hypoparathyroidism.
H th idi
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Hypoparathyroidism
Hypocalcemia occurs when there isinadequate response of the Vitamin D-PTHaxis to hypocalcemic stimuli
Hypocalcemia is often multifactorial Hypocalcemia is invariably associated with
hypoparathyroidism
Bihormonalconcomitant decrease in1,25-(OH)2-D
H th idi
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PTH-deficient hypoparathyroidism Reduced or absent synthesis of PTH
Often due to inadvertent removal of excessive
parathyroid tissue during thyroid or parathyroidsurgery
PTH-ineffective hypoparathyroidism
Synthesis of biologically inactive PTH
Hypoparathyroidism
P d h th idi
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Pseudohypoparathyroidism
PTH-resistant hypoparathyroidism Due to defect in PTH receptor-adenylate
cyclase complex
Mutation in Gs subunit Patients are also resistant to TSH, glucagon
and gonadotropins
Pseudohypoparathyroidism
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yp p y Symptoms and signs
Hypocalcemia
Hyperphosphatemia
Characteristic physical appearance: short stature, round face, shortthick neck, obesity, shortening of the metacarpals
Autosomal dominant Resistance to parathyroid hormone The patients have normal parathyroid glands, but they fail to respond
to parathyroid hormone or PTH injections The rise in urinary cAMP after parathyroid hormone fails to occur The cause of the disease is a 50% deficiency of Gs in all cells
Symptoms begin in children of about 8 years Tetany and seizures
Hypoplasia of dentin or enamel and delay or absence of eruptionoccurs in 50% of people with the disorder
Rx: vitamin D and calcium
Pseudohypoparathyroidism
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yp p y
Elfin facies, short stature,enamel hypoplasia
Hypormagnesemia by: decrease parathyroid hormone
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yp g y p ysecretion and by blunting tissue response to PTH.
Pseudohypoparathyroidism lack of response of
inadequate available PTH.1. Decerease Ca, increase phosphorus, decrease Vit D.
2. Defect in alpha subunit of G proteins (2nd messenger)
3. Administration of synthetic PTH fail to increase Ca level orincreasing excretion of phosphorus in urine.
4. There are three types- Type IA: (Alpright hereditory oasteodystrophy)
- Type IB.
- Type II.
5. Diagnostic test is by failure to increase CAMP in urine
in response to PTH infusion
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CONTINUE.. 12.Pseudohypoparathyroidism
Albright hereditary osteodystrophycharacterized by Short stature, obesity, roundface, short distal phalanges of the thumbs,brachymetacarpals and brachymetatarsals,subcutaneous calcifications, dental hypoplasia,
and developmental delay characterize thisphenotype.
Pseudopseudohypoparathyroidism (PPHP) ischaracterized by normal calcium homeostasisin the setting of the AHO phenotype.
Vit D defficiency: causes
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1. Poor intake
2. Inadequate exposure to UV light
3. Malabsorption (liver disease, GI disease,pancreatic insufficiency).
4. Increase metabolism (as in anticonvulsant thatactivate P450 system enzyme in liver that
increase degradation of vit D.5. Renal disease: CRF mainly.
6. Vitamin D dependent ricket type 1(ARabsence of one alpha hydroxylase enzyme).
7. Vitamin D dependent ricket type 2(AR defectin vit D receptor, 50% have alopecia
Redistribution of plasma Ca:
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p
1. Hyperphosphatemia due to:2. Excessive phosphate intake because of inproper formula and
decreased GFR.
3. Loading in TPN.
4. Ecessive intake by inappropriate PO4 enema or laxative.
5. Renal failure.
6. Increase endogenous phosphorus by anoxia, TLS,Rhabdomyolysis.
7. Hungry bone syndrome classicaly happen after
parathyroidectomy of hyperparathyroid tumor(decrease Ca, phosphorus and Mg).
8. Pancreatitis: break down omentum by lipase.
Citrate in transfused blood products that
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Citrate in transfused blood products that
causes binding to ionized Ca but normal
total Ca. Drugs like thiazide.
Septic shock and ICU cases: unkown
mechanism
Cli i l i t
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Clinical picture
Symptoms: Related to degree and rate of hypocalcemia.
Mild hypocalcemia is asymptomatic.
Most clinical picture due to neuromuscularirritability.
Symptoms can be provoked by
hyperventilation.
S d d h
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Symptoms depend on the age: In neonate: lethargy, vomitting, poor feeding
(sepsis picture), abdominal distention, seizure,jitterness.
In children: seizure, muscle cramp, tetany,
larygospasm, parasthesia of perioral and handarea.
Others like basal ganglia calcification in PHP,
rikets in vit D deficiency, others depend on
syndrome. Arrhythmia
Physical findings:
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y g
Hyper-reflexia (carpopedal spasm, chvostecsign- 10-20% nonspecific, trousseau sign,
stridor and cyanosis).
Abdominal distention. Seizure.
Lethargy.
Apnea. Depend on syndrome (PHP, DiGeorge, )
Diagnosis
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DiagnosisA. History
B. Lab: Serum Ca: total and ionized. Serum Mg. Phosphorus: increase in hypoparathyroidism, renal failure, others,
decrease in vit D deficiency.
Serum Lytes and glucose mainly in neonate with seizure . PTH level in serum: indicated if hypocalcemia persist in presence
of normal Mg and normal or increased phosphorus Decrease or normal in hypoparathyroidism: PTH challenge, increase Ca level.
decrease PTH due to vit D deficiency and PHP, no increase in Ca when doing
PTH challenge
Vit D (1-25 OH vit D and 25 OH vit D levels). Poorintake, malabsorption, decrease light exposure,
i b li d i d
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excessive metabolism cause decrease in 25 OH andnormal or increase or decrease 1-25 OH.
Vit D1 rickets cause normal 25 OH and decrease 1-25 OH.Vit D2 rickets causes increase in both of 25 OH and 1-25OH.
Decrease PTH causes decrease 1-25 OH
PHP causes increase 1-25 OH
Alkaline phosphatase: increase in vit D defeciency andnormal to decrease in Hypoparathyroidism.
Total protein, albumin, PH KFT
Urine Ca, Mg, PO4 and Cr in renal tubular defect andRF
T.CA I.Ca PO4 PTH
HYPOALUMEIA C
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HYPOALUMEIA DEC N N N
ALKALOSIS N DEC N N/INC
VIT D DEF DEC DEC DEC INC
CRF
DEC DEC INC INC
HYPOPTH DEC DEC INC DEC
PHP DEC DEC INC INC
PACREATITIS DEC DEC N/DEC INC
Radiology
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Radiology
CXR: loss of thymic shadow in DiGeorge syndromeand osteopenia in rickets. Wrist X-ray: rickets changes. Hand X-Ray: in PHP
Echocardiogram in DiGeorge syndrome there iscardiac anomaly.
Brain MRI: basal ganglion calcification in PHP. Renal ultrasonography: Treatment of
hypoparathyroidism can lead to nephrocalcinosis as aresult of calciuria. Baseline renal ultrasonographywith initial treatment should be performed.
D Others
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D. Others
A. ECG show prolonged QT interval
B. Malabsorption work up
C. Total lymphocytes
Treatment
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Treatment
Symptomatic hypocalcemia needs IV calcium andcontinuous monitoring for arrhythmias.
Once serum Ca is in safe range ( >7 mg/dl) IV Ca canbe stopped, and oral Ca started.
Oral Ca and vit D are initiated as soon as possible whenpatient is tolerating oral feed.
Active form of vit D is preferred in treatment of HPHor PHP and hyperphosphatemia because both impair
activation of 25 OH vit D by one alpha hydroxylase. Diet, no specific diet is required but adequate Ca and
vit D intake is recommended. (in late neonatalhypocalcemia low phosphorus formula needed likeSemilac PM 60/40.)
Calcium, intravenous
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Calcium gluconate 10% (ie, 100 mg/mL) IV solution
contains 9.8 mg/mL (0.45 mEq/mL) elemental calcium.
Calcium chloride 10% (ie, 100 mg/mL) contains 27mg/mL (1.4 mEq/mL) elemental calcium.
Calcium chloride is more irritating to the veins and
may affect pH; therefore, it is typically avoided in
pediatric patients.Dose:
10-20 mg/kg elemental calcium (1-2 mL calcium
gluconate/kg) IV slowly over 5-10 min to control
seizures; may be continued by 50-75 mg/kg/d IVinfusion over 24 h
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Use extreme care in peripheral infusion becauseextravasation can cause severe tissue necrosis.
rapid IV infusion may cause bradycardia and
hypotension.
may cause liver necrosis if administered in anumbilical venous catheter lodged in a branch of portal
vein.
prolonged use of calcium chloride may lead to
hyperchloremic acidosis
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Calcium glubionate (Neo-Calglucon) -- Calciumsupplement for PO use. The glubionate salt (1800
mg/5 mL) contains 115 mg elemental calcium/5
mL.
Dose: 50-75 mg/kg/d (as elemental calcium) PO
divided q6-8h
Use with caution in small neonates because of highosmolar load; may cause diarrhea in older children
Calcium carbonate (Oystercal, Caltrate, Tums, Os-Cal)
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Calcium carbonate (Oystercal, Caltrate, Tums, Os Cal) Supplement for PO use.
In many ways, the calcium supplement of choice because it
provides 40% elemental calcium. Thus, 1 g of calcium carbonate provides 400 mg of elemental
calcium.
Well absorbed orally and unlikely to cause diarrhea.
Available in tab and liquid forms.
Dose: -Neonates: 30-150 mg/kg/d PO divided qid; may be addedto formula (eg, Similac PM 60/40 to make a calcium-phosphorousratio of 4:1)
-Children: 20-65 mg/kg/d PO divided bid/qid
Hypercalcemia or hypercalcuria may occur when therapeuticamounts are given
Calcitriol (Rocaltrol) Active metabolic form of vitamin D (ie 1 25
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Active metabolic form of vitamin D (ie, 1,25-dihydroxycholecalciferol).
Especially useful in impaired liver or renal functioncausing inability to hydroxylate vitamin D to its activeforms.
Generally is rapidly acting.
however, may act more slowly in neonates (36-48 h).
Preterm infants may be resistant to its actions. Also used to treat acute hypocalcemia.
Dose: 0.01-0.05 mcg/kg/d IV qd/bid; adjust dosage until
normocalcemia is attainedMay cause hypercalciuria; give with calcium salts to
attain optimum results; may add hydrochlorothiazide toregimen to control hypercalciuria
Dihydrotachysterol (DHT, Hytakerol)
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Synthetic analog of vitamin D, which does not require
activation by renal 1 hydroxylase for activity.
Also available in liquid form facilitating administration
of variable doses in infants and young children.
1 mg equivalent to 120,000 U (ie, 3 mg) vitamin D-2.
Dose:Neonates: 0.05-0.1 mg/d PO
Children: 0.5-2 mg/d PO
May cause hypercalciuria; give with calcium salts to
attain optimum results; may add hydrochlorothiazide to
regimen to control hypercalciuria
Symptomatic hypocalcaemia :
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Symptomatic hypocalcaemia : In neonate: Ca gluconate of 100-200 mg/kg or
1-2ml/kg of 10% conc. Over 5-10 min & can repeated every 6 to 8 hrs , or may
continued as continuous infusion of 50-75 mg/kg over 24 hrs . In children: Ca gluconate of 100-200 mg/kg or
1-2ml/kg of 10% conc. Over 5-10 min & can repeated every 6 to 8 hrs
*The above medication should administered under cardiac monitoring .
Once symptoms resolved oral Ca used to correct serum level ,&Ca level should kept below half normal range of Ca
Tapering of oral dose depends on serum Ca level .
Ca supplement with food binds PO4 insid
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intestine so can decrease PO4 level when
used in TLS,CRF,hypoPTH . Ca supplement between meals prevent
decrease PO4so used when we have low Ca
& PO4 . Vit D used in: Malsbsorption, poor intake, and increase
metabolism with Ca supplements.
Children with CRF, HPT, PHP, and vit D1
rickets as a primary treatment
Further Outpatient Care:
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Further Outpatient Care: Carefully monitor medication dose and serum
calcium concentrations. Therapeutic goal is to
maintain serum calcium in the low-normal range
to decrease risk for nephrocalcinosis. Perform periodic renal ultrasonographic studies to
assess for nephrocalcinosis development
Certain Situations
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Certain Situations
In pacreatitis and rhabdomyolysis completecorrection of hypocalcemia should be avoidedbecause with resolution of the primary problemthere is release of the complexed Ca andhypercalcemia may happen.
If acidemia is present hypocalcemia should ifpossible be corrected first, acidemia increases theionized Ca concentration by displacing Ca fromalbumin, so the correction of acidemia causes the
ionized Ca concentration to decrease. In hypomagnesemia Mg should be corrected first Hungry bone syndrome some patients may need
supplemental phosphorus and Mg along with Ca.
Medical/Legal Pitfalls:
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Intravenous infusion with calcium-containingsolutions can cause severe tissue necrosis.
Failure to distinguish calcium receptor defects fromhypoparathyroidism
Failure to consider an associated cardiac lesion inan infant with hypocalcemia
Failure to monitor serum calcium concentrations forat least 24 hours after intravenous calciumwithdrawal (Rebound hypocalcaemia can occurwhen intravenous calcium is withdrawn, even onadequate amounts of oral calcium.)
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Causes of Hypercalcemia
Common Uncommon
Malignant disease, e.g.
some lung cancers
Renal failure
Hyperparathyroidism Sarcoidosis
Vitamin D toxicity
(excessive intake)
Multiple myeloma
Signs and Symptoms ofH l i
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Hypercalcemia
Neurologic Lethargy, drowsiness, depression, confusion Can lead to coma and death
Neuromuscular
Muscle weakness, hyptonia, decreased reflexes
Cardiac Arrhythmias
Bone Ache, pain, fracture
Primary Hyperparathyroidism
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Primary Hyperparathyroidism
Calcium homeostatic loss due to excessive PTHsecretion
Due to excess PTH secreted from adenomatous or
hyperplastic parathyroid tissue Hypercalcemia results from combined effects of
PTH-induced bone resorption, intestinal calciumabsorption and renal tubular reabsorption
Pathophysiology related to both PTH excess andconcomitant excessive production of 1,25-(OH)2-D.
Hypercalcemia of Malignancy
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Hypercalcemia of Malignancy
Underlying cause is generally excessive bone
resorption by one of three mechanisms
1,25-(OH)2-D synthesis by lymphomas Local osteolytic hypercalcemia 20% of all hypercalcemia of malignancy
Humoral hypercalcemia of malignancy Over-expression of PTH-related protein (PTHrP)
Hypercalcemia of Malignancy
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Hypercalcemia of Malignancy
Treatment improves quality of life when
Ca2+ is elevated but not yet life threatening
Treat with bisphosphonates Inhibits osteoclastic activity
When serum Ca2+ > 3.00 mM treat with
NaCl IV
PTH receptor defect
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PTH receptor defect
Rare disease known as Jansensmetaphyseal chondrodysplasia
Characterized by hypercalcemia,
hypophosphotemia, short-limbed dwarfism Due to activating mutation of PTH receptor
Rescue of PTH receptor knock-out with
targeted expression of Jansens transgene
Osteoporosis
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p
Osteoporosis is characterized by a significant reduction in bonemineral density compared with age- and sex-matched norms
There is a decrease in both bone mineral and bone matrix
Osteoporosis is the most common metabolic bone disease
Affects 20 million Americans and leads to 1.3 million fractures in theUS per year
Women lose 50% of their trabecular bone and 30 % of their cortical
bone
30% of all postmenapausal women will sustain an osteoporoticfracture as will 1/6th of all men
The cost of health care and lost productivity is $14 billion in the US
annually
Normal and Osteoporotic Bone
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No a a d Osteopo ot c o e
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Sequelae of
Osteoporosis
Bone Density as a Function of Age
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FDA Approved Rxs for Osteoporosis
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Bisphosphonates (alendronate and risedronate),
calcitonin, estrogens, parathyroid hormone andraloxifene are approved by the US Food and DrugAdministration (FDA) for the prevention and/ortreatment of osteoporosis
The bisphosphonates (alendronate and risedronate),calcitonin, estrogens and raloxifene affect the boneremodeling cycle and are classified as anti-resorptivemedications
Teriparatide, a form of parathyroid hormone, is a
newly approved osteoporosis medication. It is the firstosteoporosis medication to increase the rate of boneformation in the bone remodeling cycle
Treatments (Continued) Exercise, activity
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Exercise, activity
Calcium intake should be 1000-1500 mg/day
Postmenapausal women take in less than 500 mg/day
Males and females should take in 1000-1500 mg/day
All adults greater than 65 years should take 1500 mg/day
Three glasses of milk or three cups of yogurt per day provide 1000-1500
mg/day
Estrogen treatment Estrogen inhibits osteoclastic activity
Bone density increases 3-5% per year for the first three years after menopause
This therapy needs to be individualized Estrogen may increase the incidence of breast cancer, heart attacks, stroke, blood clots
That it may exacerbate cardiovascular disease is controversial
All the data are not in yet, and estrogen treatment is under review; for more
information go to http://www.fda.gov/bbs/topics/NEWS/2003/NEW00863.html
Treatments (Continued) R l if (B d E i t ) i l ti t t
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Raloxifene (Brand name Evista) is a selective estrogen receptormodulator
Decreases in estrogen levels after menopause lead to increases in boneresorption and bone loss. Bone is initially lost rapidly because thecompensatory increase in bone formation is inadequate to offsetresorptive losses. This imbalance between resorption and formation isrelated to loss of estrogen, and may also involve age-related
impairment of osteoblasts or their precursors Raloxifene reduces resorption of bone and decreases overall bone
turnover. These effects on bone are manifested as increases in bonemineral density (BMD)
Raloxifenes biological actions, like those of estrogen, are mediatedthrough binding to estrogen receptors. This binding results in themodulation of expression of multiple estrogen-regulated genes indifferent tissues
Treatments (Continued)
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Bisphosphonates inhibit osteroclasts Alendronate (Brand name Fosamax)
Risedronate (Brand name Actonel)
Calcitonin (Brand name Miacalcin )
From salmon
Given intranasaly Probably least effective Rx
Vitamin D
Most Americans consume less than recommended amount
800 IU per day seems safe and not enough to cause vitamin Dtoxicity
Treatments (Continued)
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Parathyroid hormone (Brand name Forteo) Teriparatide, a form of parathyroid hormone, is approved for the treatment of
osteoporosis in postmenopausal women and men who are at high risk for afracture
Chronically elevated PTH leads to bone loss; however, intermittent PTH(once daily bolus injection) leads to new bone synthesis
Must be injected daily, a major disadvantage
Cost about $7000 per year Future Rxs Sodium fluoride
Considered a possibility for years
Adoption seems unlikely
Strontium ranelate
NEJM 350 (2004) 459-468.
Calcium Content of Foods
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http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/
http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.htmlhttp://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.html -
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Thank You