Calcium homeostasis is regulated by parathyroid hormone (PTH), calcitonin, and vitamin D3. PTH increases calcium absorption in the intestine and calcium release from bone by stimulating vitamin D conversion to its active form. Vitamin D increases intestinal calcium absorption and bone calcium resorption. Calcium levels directly regulate PTH secretion from the parathyroid glands. Together this hormonal system tightly controls extracellular calcium levels.
Insulin Lispro Revisited
By Dr. Usama Ragab Youssif
The discovery of insulin was one of the most dramatic and important milestones in medicine - a Nobel Prize-winning moment in science.
In patients with carotid artery stenosis what is the best method of approaching carotid repair, surgical or minimally invasive?
After research including medical journals such as AHA, ACC guidelines and Cochrane library the answer is inconclusive.
Presentation given to our fellowship program about diabetic kidney disease.
2022 update discussing SGLT2i, MRA (e.g. finerenone), health economics and beyond
Insulin Lispro Revisited
By Dr. Usama Ragab Youssif
The discovery of insulin was one of the most dramatic and important milestones in medicine - a Nobel Prize-winning moment in science.
In patients with carotid artery stenosis what is the best method of approaching carotid repair, surgical or minimally invasive?
After research including medical journals such as AHA, ACC guidelines and Cochrane library the answer is inconclusive.
Presentation given to our fellowship program about diabetic kidney disease.
2022 update discussing SGLT2i, MRA (e.g. finerenone), health economics and beyond
Overall description of bone metabolism.
Introduction
Types of bone tissue
Composition of bone
Cells of bone
Regulators of bone metabolism
Calcium and phosphate balance
Calcium and phosphate
Parathyroid hormone
Calcitonin
Vitamin D
Fibroblast growth factor
Growth hormone and IGF-1
Thyroid hormone
Estrogens, progesterone and androgens
Cortisol and related glucocorticoids
Disorders of bone metabolism
Orthodontic considerations
Introduction to calcium
Sources of calcium
Dietary requirement of calcium
Calcium absorption
Biochemical function of calcium
Calcium in blood
Calcium estimation
Factors regulating calcium level in blood
Disease states of calcium
Ppt file for hematology concepts.
Because such a large amount of calcium is stored in bone, it is the most abundant mineral in the body. Our bodies contain 1200 g of calcium.
About 98% of the calcium in adults is located in the skeleton and teeth, where it is combined with phosphates to form a crystal lattice of mineral salts, hydroxyapatite, Ca10(PO4)6(OH)2.
In addition, calcium helps to stabilize cell membranes and is essential for the release of neurotransmitters from neurons and of hormones from endocrine glands.
Calcium is absorbed through the intestines under the influence of activated vitamin D. A deficiency of vitamin D leads to a decrease in absorbed calcium and, eventually, a depletion of calcium stores from the skeletal system, potentially leading to rickets in children and osteomalacia in adults, contributing to osteoporosis.
Hypocalcemia, bicarbonate, calcium magnesium zinc oxide
The kidneys are the main regulators of blood HCO3− concentration.
The intercalated cells of the renal tubule can either form HCO3− and release it into the blood when the blood level is low or excrete excess HCO3− in the urine when the level in blood is too high.
PTH stimulates resorption of bone extracellular matrix by osteoclasts, which releases both phosphate and calcium ions into the bloodstream.
In the kidneys, however, PTH inhibits reabsorption of phosphate ions while stimulating reabsorption of calcium ions by renal tubular cells.
Thus, PTH increases urinary excretion of phosphate and lowers blood phosphate level.
Describe the normal values of Calcium in plasma
Describe the bone remodeling and its significance
Discuss the role of Pyrophosphate, NPP1 , ANK & TNAP
Explain the mechanism of bone resorption
Describe the actions of Vitamin D
Describe Rickets and Osteomalacia
Indian Dental Academy: will be one of the most relevant and exciting training center with best faculty and flexible training programs for dental professionals who wish to advance in their dental practice,Offers certified courses in Dental implants,Orthodontics,Endodontics,Cosmetic Dentistry, Prosthetic Dentistry, Periodontics and General Dentistry.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
Overall description of bone metabolism.
Introduction
Types of bone tissue
Composition of bone
Cells of bone
Regulators of bone metabolism
Calcium and phosphate balance
Calcium and phosphate
Parathyroid hormone
Calcitonin
Vitamin D
Fibroblast growth factor
Growth hormone and IGF-1
Thyroid hormone
Estrogens, progesterone and androgens
Cortisol and related glucocorticoids
Disorders of bone metabolism
Orthodontic considerations
Introduction to calcium
Sources of calcium
Dietary requirement of calcium
Calcium absorption
Biochemical function of calcium
Calcium in blood
Calcium estimation
Factors regulating calcium level in blood
Disease states of calcium
Ppt file for hematology concepts.
Because such a large amount of calcium is stored in bone, it is the most abundant mineral in the body. Our bodies contain 1200 g of calcium.
About 98% of the calcium in adults is located in the skeleton and teeth, where it is combined with phosphates to form a crystal lattice of mineral salts, hydroxyapatite, Ca10(PO4)6(OH)2.
In addition, calcium helps to stabilize cell membranes and is essential for the release of neurotransmitters from neurons and of hormones from endocrine glands.
Calcium is absorbed through the intestines under the influence of activated vitamin D. A deficiency of vitamin D leads to a decrease in absorbed calcium and, eventually, a depletion of calcium stores from the skeletal system, potentially leading to rickets in children and osteomalacia in adults, contributing to osteoporosis.
Hypocalcemia, bicarbonate, calcium magnesium zinc oxide
The kidneys are the main regulators of blood HCO3− concentration.
The intercalated cells of the renal tubule can either form HCO3− and release it into the blood when the blood level is low or excrete excess HCO3− in the urine when the level in blood is too high.
PTH stimulates resorption of bone extracellular matrix by osteoclasts, which releases both phosphate and calcium ions into the bloodstream.
In the kidneys, however, PTH inhibits reabsorption of phosphate ions while stimulating reabsorption of calcium ions by renal tubular cells.
Thus, PTH increases urinary excretion of phosphate and lowers blood phosphate level.
Describe the normal values of Calcium in plasma
Describe the bone remodeling and its significance
Discuss the role of Pyrophosphate, NPP1 , ANK & TNAP
Explain the mechanism of bone resorption
Describe the actions of Vitamin D
Describe Rickets and Osteomalacia
Indian Dental Academy: will be one of the most relevant and exciting training center with best faculty and flexible training programs for dental professionals who wish to advance in their dental practice,Offers certified courses in Dental implants,Orthodontics,Endodontics,Cosmetic Dentistry, Prosthetic Dentistry, Periodontics and General Dentistry.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
2. Physiological Importance of Calcium
• Ca is the most abundant mineral in the body.
• Ca salts in bone provide structural integrity of the
skeleton.
• The amount of Ca is balanced 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 are essential
to normal function of a host of biochemical processes
– Neuoromuscular excitability and signal transduction
– Blood coagulation
– Hormonal secretion
– Enzymatic regulation
– Neuron excitation
3. 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.
4. Storage of Calcium
• The primary site of storage is our bones (about
1000 grams).
• Some calcium is stored within cells.
• Bone is produced by osteoblast cells which
produce collagen, which is then mineralized by
calcium and phosphate (hydroxyapatite).
• Bone is remineralized (broken down) by
osteoclasts, which secrete acid, causing the
release of calcium and phosphate into the
bloodstream.
• There is constant exchange of calcium
between bone and blood.
5. 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.
6. Regulation of [Calcium]
• The important role that calcium plays in
so many processes dictates that its
concentration, both extracellularly and
intracellularly, be maintained within a
very narrow range.
• This is achieved by an elaborate system
of controls.
7. • Control of cellular Ca homeostasis is as
carefully maintained in extracellular fluids
• [Ca2+]cyt is approximately 1/1000th of
extracellular concentration
• Stored in mitochondria and ER
• “pump-leak” transport systems control
[Ca2+]cyt
– Calcium leaks into cytosolic compartment and is
actively pumped into storage sites in organelles to
shift it away from cytosolic pools.
Regulation of Intracellular [Calcium]
8.
9. Extracellular Calcium
• When extracellular calcium falls below
normal, the nervous system becomes
progressively more excitable because of
increase permeability of neuronal
membranes to sodium.
• Hyperexcitability causes tetanic
contractions
– Hypercalcemic tetany [Ca2+]cyt
10. • 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
11. • Binding of calcium to albumin is pH
dependent.
• Acute alkalosis increases calcium binding to
protein and decreases ionized calcium.
• Patients who develop acute respiratory
alkalosis have 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
12. Calcium and Phosphorous
• Ca is tightly regulated with P in the
body.
• P is an essential mineral necessary for
ATP, cAMP 2nd messenger systems,
and other roles.
14. Calcium in Blood and Bone
• Ca2+ normally ranges from 8.5-10
mg/dL in 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 to salt.
• Only free, ionized Ca2+ is biologically
active.
16. 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.
17. Calcium and Bone
• 99% of Ca is found in the bone. Most is
found in hydroxyapatite crystals. Very
little Ca2+ can be released from the
bone– though it is the major reservoir of
Ca2+ in the body.
19. Calcium Turnover in Bones
• 80% of bone is mass consists of cortical
bone– for example: dense concentric layers
of appendicular skeleton (long bones).
• 20% of bone mass consists of trabecular
bone– bridges of bone spicules of the axial
skeleton (skull, ribs, vertebrae, pelvis).
• Trabecular bone has 5 X greater surface
area, though comprises lesser mass.
• Because of greater accessibility trabecular
bone is more important to calcium turnover.
20. Bones
• 99% of the Calcium in our bodies is found in our
bones which serve as a reservoir for Ca2+ storage.
• 10% of total adult bone mass turns over each year
during remodeling process
• During growth rate of bone formation exceeds
resporption and skeletal mass increases.
• Linear growth occurs at epiphyseal plates.
• Increase in width occurs at periosteum
• Once adult bone mass is achieved equal rates of
formation and resorption maintain bone mass until
age of about 30 years when rate of resportion begins
to exceed formation and bone mass slowly
decreases.
21. Types of Bone Cells
• There are 3 major types of bone cells:
Osteoblasts are the differentiated bone
forming cells and secrete bone matrix on
which Ca2+ and PO4
3- precipitate.
• Osteocytes, the mature bone cells are
enclosed in bone matrix.
• Osteoclasts is a large multinucleated cell
derived from monocytes whose function is to
resorb bone. Inorganic bone is composed of
hydroxyapatite and organic matrix is
composed primarily of collagen.
22. Bone Formation
• Active osteoblasts synthesize and
extrude collagen.
• Collagen fibrils form arrays of an
organic matrix called the osetoid.
• Calcium phosphate is deposited in the
osteoid and becomes mineralized.
• Mineralization is combination of CaPO4,
OH-, and H2CO3
– hydroxyapatite.
23. Mineralization
• Requires adequate Calcium and
phosphate.
• Dependent on Vitamin D.
• Alkaline phosphatase and osteocalcin
play roles in bone formation.
• Their plasma levels are indicators of
osteoblast activity.
24. Canaliculi
• Within each bone unit is a minute fluid-
containing channel called the canaliculi.
• Canaliculi traverse the mineralized bone.
• Interior osteocytes remain connected to
surface cells via syncytial cell processes.
• This process permits transfer of calcium
from enormous surface area of the interior
to extracellular fluid.
26. Control of Bone Formation and
Resorption
• Bone resorption of Ca2+ by two mechanims:
osteocytic osteolysis is a rapid and transient
effect and osteoclasitc resorption which is
slow and sustained.
• Both are stimulated by PTH. CaPO4
precipitates out of solution id its solubility is
exceeded. The solubility is defined by the
equilibrium equation: Ksp = [Ca2+]3[PO4
3-]2.
• In the absence of hormonal regulation plasma
Ca2+ is maintained at 6-7 mg/dL by this
equilibrium.
27. Osteocytic Osteolysis
• Transfer of calcium from canaliculi to
extracellular fluid via activity of
osteocytes.
• Does not decrease bone mass.
• Removes calcium from most recently
formed crystals.
• Happens quickly.
28. Bone Resorption
• Does not merely extract calcium, it
destroys entire matrix of bone and
diminishes bone mass.
• Cell responsible for resorption is the
osteoclast.
29. Bone Remodeling
• Endocrine signals to resting osteoblasts generate
paracrine signals to osteoclasts and precursors.
• Osteoclasts resorb and area of mineralized bone.
• Local macrophages clean up debris.
• Process reverses when osteoblasts and
precursors are recruited to site and generate new
matrix.
• New matrix is minearilzed.
• New bone replaces previously resorbed bone.
31. Calcium, Bones and Osteoporosis
• The total bone mass of humans peaks
at 25-35 years of age.
• Men have more bone mass than
women.
• A gradual decline occurs in both
genders with aging, but women undergo
an accelerated loss of bone due to
increased resorption during
perimenopause.
• Bone resorption exceeds formation.
32. • Reduced bone density and mass:
osteoporosis
• Susceptibility to fracture.
• Earlier in life for women than men but
eventually both genders succumb.
• Reduced risk:
– Calcium in the diet
– habitual exercise
– avoidance of smoking and alcohol intake
– avoid drinking carbonated soft drinks
Calcium, Bones and Osteoporosis
33. Vertebrae of 40- vs. 92-year-old
women
Note the marked loss of trabeculae with preservation of cortex.
35. 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.
36. Vitamin D
• Vitamin D, after its activation to the
hormone 1,25-dihydroxy Vitamin D3 is a
principal regulator of Ca2+.
• Vitamin D increases Ca2+ absorption
from the intestine and Ca2+ resorption
from the bone .
37. Synthesis of Vitamin D
• Humans acquire vitamin D from two sources.
• Vitamin D is produced in the skin by
ultraviolet radiation and ingested in the diet.
• Vitamin D is not a classic hormone because it
is not produce and secreted by an endocrine
“gland.” Nor is it a true “vitamin” since it can
be synthesized de novo.
• Vitamin D is a true hormone that acts on
distant target cells to evoke responses after
binding to high affinity receptors
38. • Vitamin D3 synthesis occurs in keratinocytes
in the skin.
• 7-dehydrocholesterol is photoconverted to
previtamin D3, then spontaneously converts
to vitamin D3.
• Previtamin D3 will become degraded by over
exposure to UV light and thus is not
overproduced.
• Also 1,25-dihydroxy-D (the end product of
vitamin D synthesis) feeds back to inhibit its
production.
Synthesis of Vitamin D
39. • PTH stimulates vitamin D synthesis. In the
winter or if exposure to sunlight is limited
(indoor jobs!), then dietary vitamin D is
essential.
• Vitamin D itself is inactive, it requires
modification to the active metabolite, 1,25-
dihydroxy-D.
• The first hydroxylation reaction takes place in
the liver yielding 25-hydroxy D.
• Then 25-hydroxy D is transported to the
kidney where the second hydroxylation
reaction takes place.
Synthesis of Vitamin D
40. • The mitochondrial P450 enzyme 1a-
hydroxylase converts it to 1,25-dihydroxy-D,
the most potent metabolite of Vitamin D.
• The 1a-hydroxylase enzyme is the point of
regulation of D synthesis.
• Feedback regulation by 1,25-dihydroxy D
inhibits this enzyme.
• PTH stimulates 1a-hydroxylase and
increases 1,25-dihydroxy D.
Synthesis of Vitamin D
41. • 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 1a-hydroxylase and
decreased levels of PO4 stimulate 1a-
hydroxylase activity
Synthesis of Vitamin D
42. 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).
43. Regulation of Vitamin D by PTH and
Phosphate Levels
PTH
25-hydroxycholecalciferol 1,25-
dihydroxycholecalciferol
1-hydroxylase
Low phosphate
increase
phosphate
resorption
45. Vitamin D
• Vitamin D is a lipid soluble hormone that
binds to a typical nuclear receptor, analogous
to steroid hormones.
• Because it is lipid soluble, it travels in the
blood bound to hydroxylated a-globulin.
• There are many target genes for Vitamin D.
46.
47. Vitamin D action
• The main action of 1,25-(OH)2-D is to
stimulate absorption of Ca2+ from the
intestine.
• 1,25-(OH)2-D induces the production of
calcium binding proteins which sequester
Ca2+, buffer high Ca2+ concentrations that
arise during initial absorption and allow Ca2+
to be absorbed against a high Ca2+ gradient
48. 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
49. Clinical correlate
• Vitamin D-dependent rickets type II
• Mutation in 1,25-(OH)2-D receptor
• Disorder characterized by impaired
intestinal calcium absorption
• Results in rickets or osteomalacia
despite increased levels of 1,25-(OH)2-
D in circulation
50. Vitamin D Actions on Bones
• Another important target for 1,25-(OH)2-D is
the bone.
• Osteoblasts, but not osteoclasts have vitamin
D receptors.
• 1,25-(OH)2-D acts on osteoblasts which
produce a paracrine signal that activates
osteoclasts to resorb Ca++ from the bone
matrix.
• 1,25-(OH)2-D also stimulates osteocytic
osteolysis.
51. Vitamin D and Bones
• Proper bone formation is stimulated by
1,25-(OH)2-D.
• In its absence, excess osteoid
accumulates from lack of 1,25-(OH)2-D
repression of osteoblastic collagen
synthesis.
• Inadequate supply of vitamin D results
in rickets, a disease of bone
deformation
52. Parathyroid Hormone
• PTH is synthesized and secreted by the
parathyroid gland which lie posterior to
the thyroid glands.
• The blood supply to the parathyroid
glands is from the thyroid arteries.
• The Chief Cells in the parathyroid gland
are the principal site of PTH synthesis.
• It is THE MAJOR of Ca homeostasis in
humans.
54. Synthesis of PTH
• PTH is translated as a pre-prohormone.
• Cleavage of leader and pro-sequences
yield a biologically active peptide of 84
aa.
• Cleavage of C-terminal end yields a
biologically inactive peptide.
55. Regulation of PTH
• The dominant regulator of PTH is
plasma Ca2+.
• 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 is maximally inhibited.
57. • PTH secretion responds to small alterations in
plasma Ca2+ within seconds.
• A unique calcium receptor within the parathyroid
cell plasma membrane senses changes in the
extracellular fluid concentration of Ca2+.
• This is a typical G-protein coupled receptor that
activates phospholipase C and inhibits adenylate
cyclase—result is increase in intracellular Ca2+
via generation of inositol phosphates and
decrease in cAMP which prevents exocytosis of
PTH from secretory granules.
Regulation of PTH
58. • When Ca2+ falls, cAMP rises and PTH is
secreted.
• 1,25-(OH)2-D inhibits PTH gene
expression, providing another level of
feedback control of PTH.
• Despite close connection between Ca2+
and PO4, no direct control of PTH is
exerted by phosphate levels.
Regulation of PTH
60. PTH action
• The overall action of PTH is to increase
plasma Ca2+ levels and decrease plasma
phosphate levels.
• PTH acts directly on the bones to stimulate
Ca2+ resorption and kidney to stimulate Ca2+
reabsorption in the distal tubule of the kidney
and to inhibit reabosorptioin of phosphate
(thereby stimulating its excretion).
• PTH also acts indirectly on intestine by
stimulating 1,25-(OH)2-D synthesis.
62. Actions of PTH: Bone
• PTH acts to increase degradation of bone
(release of calcium).
- causes osteoblasts to release cytokines, which
stimulate osteoclast activity
- stimulates bone stem cells to develop into
osteoclasts
- net result: increased release of calcium from
bone
- effects on bone are dependent upon presence
of vitamin D
63. Actions of PTH: Kidney
• PTH acts on the kidney to increase the
reabsorption of calcium (decreased excretion).
• Also get increased excretion of phosphate (other
component of bone mineralization), and
decreased excretion of hydrogen ions (more
acidic environment favors dimineralization of
bone)
• And, get increased production of the active
metabolite of vitamin D3 (required for calcium
absorption from the small intestine, bone
demineralization).
• NET RESULT: increased plasma calcium levels
64.
65. 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
66. 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).
69. PTH-Related Peptide
• Has high degree of homology to PTH, but is not
from the 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?
70. Primary Hyperparathyroidism
• Calcium homeostatic loss due to excessive
PTH secretion
• Due to excess PTH secreted from
adenomatous or hyperplastic parathyroid tissue
• Hypercalcemia results from combined effects of
PTH-induced bone resorption, intestinal
calcium absorption and renal tubular
reabsorption
• Pathophysiology related to both PTH excess
and concomitant excessive production of 1,25-
(OH)2-D.
71. 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)
72. PTHrP
• Three forms of PTHrP identified, all
about twice the size of native PTH
• Marked structural homology with PTH
• PTHrP and PTH bind to the same
receptor
• PTHrP reproduce full spectrum of PTH
activities
73. PTH receptor defect
• Rare disease known as Jansen’s
metaphyseal 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 “Jansen’s
74. Hypoparathyroidism
• Hypocalcemia occurs when there is
inadequate response of the Vitamin D-
PTH axis to hypocalcemic stimuli
• Hypocalcemia is often multifactorial
• Hypocalcemia is invariably associated
with hypoparathyroidism
• Bihormonal—concomitant decrease in
1,25-(OH)2-D
75. • PTH-deficient hypoparathyroidism
– Reduced or absent synthesis of PTH
– Often due to inadvertent removal of
excessive parathyroid tissue during thyroid
or parathyroid surgery
• PTH-ineffective hypoparathyroidism
– Synthesis of biologically inactive PTH
Hypoparathyroidism
79. Calcitonin
• Calcitonin acts to decrease plasma Ca2+
levels.
• While PTH and vitamin D act to increase
plasma Ca2+-- only calcitonin causes a
decrease in plasma Ca2+.
• Calcitonin is synthesized and secreted by the
parafollicular cells of the thyroid gland.
• They are distinct from thyroid follicular cells
by their large size, pale cytoplasm, and small
secretory granules.
80. • 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
81. • The target cell for calcitonin is the
osteoclast.
• Calcitonin acts via increased cAMP
concentrations to inhibit osteoclast
motility and cell shape and inactivates
them.
• The major effect of calcitonin
administration is a rapid fall in Ca2+
caused by inhibition of bone resorption.
Calcitonin
82. 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 t
release Ca
Decreased
resorption
83. • Role of calcitonin in normal Ca2+ control is not
understood—may be more important in control of
bone remodeling.
• Used clinically in treatment of hypercalcelmia and in
certain bone diseases in which sustained reduction of
osteoclastic resorption is therapeutically
advantageous.
• Chronic excess of calcitonin does not produce
hypocalcemia and removal of parafollicular cells does
not cause hypercalcemia. PTH and Vitamin D3
regulation dominate.
• May be more important in regulating bone remodeling
than in Ca2+ homeostasis.
Calcitonin
84. Regulation of Calcitonin Release
• Calcitonin release is stimulated by increased
circulating plasma calcium levels.
• Calcitonin release is also caused by the
gastrointestinal hormones gastrin and
cholecystokinin (CCK), whose levels increase
during digestion of food.
Food (w/ Ca?)
gastrin, CCK
increased
calcitonin
decreased bone
resorption
85. 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).
86. 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.
87. Other Factors Influencing Bone and
Calcium Metabolism
• Estrogens and Androgens: both stimulate
bone formation 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
bone fractures.
88. Findings of NIH Consensus Panel on
Osteoporosis
• The National Institutes of Health has concluded
the following:
• Adequate calcium and vitamin D intake are
crucial to develop optimal peak bone mass and
to preserve bone mass throughout life.
• Factors contributing to low calcium intakes are
restriction of dairy products, a generally low
level of fruit and vegetable consumption, and a
high intake of low calcium beverages such as
sodas.
89. Influences of Growth Hormone
• Normal GH levels are required for skeletal growth.
• GH increases intestinal calcium absorption and renal
phosphate resorption.
• Insufficient GH prevents normal bone production.
• Excessive GH results in bone abnormalities
(acceleration of bone formation AND resorption).
90. Effects of Glucocorticoids
• Normal levels of glucocorticoids (cortisol) are
necessary for skeletal growth.
• Excess glucocorticoid levels decrease renal calcium
reabsorption, interfere with intestinal calcium
absorption, and stimulate PTH secretion.
• High glucocorticoid levels also interfere with growth
hormone production and action, and gonadal steroid
production.
• Net Result: rapid osteoporosis (bone loss).
91. Influence of Thyroid Hormones
• Thyroid hormones are important in skeletal growth
during infancy and childhood (direct effects on
osteoblasts).
• Hypothyroidism leads to decreased bone growth.
• Hyperthyroidism can lead to increased bone loss,
suppression of PTH, decreased vitamin D
metabolism, decreased calcium absorption. Leads to
osteoporosis.
92. Effects of Diet
• Increasing dietary intake of Ca may prevent
osteoporosis in postmenopausal women.
• Excessive Na intake in diet can impair renal Ca
reabsorption, resulting in lower blood Ca and
increased PTH release. Normally, PTH results in
increased absorption of Ca from the GI tract (via
vitamin D). But in aging women, vitamin D
production decreases, so Ca isn’t absorbed, and PTH
instead causes increased bone loss.
• High protein diet may cause loss of Ca from bone,
due to acidic environment resulting from protein
metabolism and decreased reabsorption at the
kidney.
93. Nutrition and Calcium
Heaney RP, Refferty K Am J. Clin Nutr
200174:343-7
– Excess calciuria associated with consumption of
carbonated beverages is confined to caffeinated
beverages.
– Acidulant type (phosphoric vs. citric acid) has no
acute effect.
– The skeletal effects of carbonated beverage
consumption are due primarily to milk
displacement.
94. Nutrition and Calcium
See Nutrition 2000 Vol 16 (7/8) in particular:
• Calvo MS “Dietary considerations to prevent
loss of bone and renal function”
– “overall trend in food consumption in the US is to drink less
milk and more carbonated soft drinks.”
– “High phosphorus intake relative to low calcium intake”
– Changes in calcium homeostasis and PTH regulation that
promote bone loss in children and post-menopausal women.
– High sodium associated with fast-food consumption
competes for renal reabsorption of calcium and PTH
secretion.
95. Nutrition and Calcium
See Nutrition 2000 Vol 16 (7/8) in particular:
• Harland BF “Caffeine and Nutrition”
– Caffeine is most popular drug consumed world-
wide.
– 75% comes from coffee
– Deleterious effects associated with pregnancy and
osteoporosis.
• Low birth-rate and spontaneous abortion with excessive
consumption
• For every 6 oz cup of coffee consumed there was a net
loss of 4.6 mg of calcium
• However, if you add milk to your coffee, you can replace
the calcium that is lost.
96. Effects of soft drinks
• Intake of carbonated beverages has been
associated with increased excretion and loss
of calcium
• 25 years ago teenagers drank twice as much
milk as soda pop. Today they drink more than
twice as much soda pop as milk.
• Another significant consideration is obesity
and increased risk for diabetes.
• For complete consideration of ill effects of soft
drinks on health and environment see:
– http://www.saveharry.com/bythenumbers.html
97. Excessive sodium intake
• Excessive intake of Na may cause renal
hypercalciuria by impairing Ca reabsorption
resulting in compensatory increase in PTH
secretion.
• Stimulation of intestinal Ca absorption by
PTH-induced 1,25-(OH)2-D production
compensates for excessive Ca excretion
• Post-menopausal women at greater risk for
bone loss due to excessive Na intake due to
impaired vitamin D synthesis which
accompanies estrogen deficiency.
98. Effects of Exercise
• Bone cells respond to pressure
gradients in laying down bone.
• Lack of weight-bearing exercise decreases
bone formation, while increased exercise helps
form bone.
•
Increased bone resorption during immobilization may
result in hypercalcemia
99. Exercise and Calcium
• Normal bone function requires weight-
bearing exercise
• Total bed-rest causes bone loss and
negative calcium balance
• Major impediment to long-term space
travel