Hormonal Regulation Of Plasma Calcium And Calcium Metabolism

Guo Xiaosun

guoxiaosun@126.com

Shandong University

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• 1. The significance of maintaining plasma calcium levels.

• I The normal value and source of plasma calcium;

• II The structure, functions and endocrinology of bone;

• 2. The hormonal regulation of plasma calcium:

• I Parathyroid hormone: parathyroid glands; secretion of parathyroid hormone; actions of parathyroid hormone; parathyroid hormone related peptide.

• II Calcitriol: source and activation of vitamin D; vitamin D and calcitriol in blood ； action of calcitriol.

• III other hormones.

• 3. Disorders of calcium metabolism and metabolic bone disease:

• I Disorders of hypocalcaemia: vitamin D deficiency; parathyroid hormone deficiency.

• II Diseases of bone: osteoporosis; osteomalacia and rickets; Paget’s disease.

• 4. Regulation of serum phosphate. 2

1.The significance of maintaining plasma calcium levels.

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CALCIUM

•2% of body weight 99% in bones 1% in body fluids

•Plasma (Extracellular fluid)

▫2.25 – 2.75 mmol/l

•Cell (Intracellular fluid)

▫10-8 – 10-7 mol/l = 10-5 – 10-4 mmol/l

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PLASMA CALCIUM diffusible

• 48% (50%) Ca2+ ionized

• 6% (10%) combined with anions

(citrate, phosphate) – non-

dissociated

nondiffusible

• 46% (40%) combined with plasma

proteins

• combination with proteins depends

on pH 0.2 mmol/l Ca2+ on each pH

unit

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Plasma Calcium Regulation

•Free calcium is tightly regulated (5%)

▫Too low = neuronal hyper-excitability

▫Too high = neuronal depression

•Control points for calcium

▫Absorption – Via intestines

▫Excretion – Via urine

▫Temporary storage – Via bones

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Calcium Balance• Intake = output•Negative calcium

balance: Output > intake▫Neg Ca2+ balance

leads to osteoporosis•Positive calcium

balance: Intake > output▫Occurs during growth

•Calcium is essential, we can’t synthesize it

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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 9

ROLE OF CALCIUM

• excitability of cell membranes

• neuromuscular transmission and muscle contraction

• releasing of transmitters from synapses

• “second messenger”

• stimulates secretory activity of exocrine glands and

releasing of hormones

• contractility of myocard

• blood coagulation

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Changes in Ca2+ plasma levelHypocalcemia

• Muscle tetany carpopedal spasm

• Na+ inflow ↑→myocardium excitability and conductibility ↑ ；Ca2+ inflow ↓→plateau phase of action potential↑

• Increased cell membrane permeability

• Impaired blood clotting

Hypercalcemia

• Depression of nervous system, reflex activity,

• Increased heart contractility

• Formation of calcium phosphate crystalls （ Kidney stones, and

ectopic calcification）

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Bones – reservoir of calcium• 99% of skeletal calcium forms stable bone (not

exchangeable with the Ca in extracellular fluid)

• 1% is in the form of releasable pool of Ca

• Balance of deposition and resorption

• Osteoblasts – bone-forming cells responsible for

bone deposition

▫Secrete type I collagen

▫Differentiate into osteosytes

• Osteoclasts – “bone-eating” cells that resorb the

previously formed bone12

Osteoblast and Osteoclast Function

• Osteoblasts

• Bone formation

• Synthesis of matrix

proteins

▫ Type I collagen

▫ Osteocalcin

▫ Others

• Mineralization

• Activation of osteoclasts

via RANKL production

• Osteoclasts

• Bone resorption

▫ Degradation of proteins by

enzymes

▫ Acidification

• RANK is activated by

RANKL, and this leads to

cells differentiation to

osteoclasts

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Regulation of osteoblasts function

• Stimulation▫PTH (fast reaction - activation of calcium pump ? –

pumping Ca to ECF)▫1,25 Dihydrocholecalciferol▫ IL-1▫T3, T4▫hGH, IGF-1 (insuline-like growth factor)▫PGE2 (prostaglandine)

▫TNF (tumor necrosis factor)▫Estrogens

• Inhibition▫Corticosteroids

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Regulation of osteoclasts function• Stimulation

▫PTH (not directly – through stimulation of osteoblasts)

▫1,25 Dihydrocholecalciferol (not directly – through stimulation of osteoblasts)

▫ IL-6, IL-11• Inhibition

▫Calcitonin (directly – receptors)▫Estrogens (by inhibiting production of certain

cytokines)▫TGF-β (tranforming growth factor)▫PGE2(prostaglandine)

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2. The hormonal regulation of plasma calcium

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Regulation of calcium metabolism

1. Parathyroid hormone

2. Calcitonin

3. Vitamin D

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Parathormon

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Parathyroid Hormone Structure• Synthesized in the 4 para-thyroid glands

• PreProPTH Regulator of Ca2+ homeostasis

• 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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Parathyroid Glands

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28W.F.Ganong: Review of Medical Physiology 2003 20th Ed. #188 fig.21-10

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

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Actions of PTH: Bone

• PTH acts to increase degradation of bone (release of calcium).

--Rapid action

--Delayed action

- 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

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Actions of PTH: Kidney• PTH acts on the kidney → the reabsorption of calcium ↑

(excretion↓).

• excretion of phosphate ↑ excretion of H +↓ (more acidic

environment favors demineralization of bone)

• ALSO, Stimulates transcription of 1-alpha hydroxylase for

Vitamin D activation in kidney→the active metabolite of

vitamin D3↑ (required for calcium absorption from the small

intestine, bone demineralization).

• NET RESULT: increased plasma calcium levels

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Regulation of PTH Secretion

• PTH is released in response to changes in plasma calcium

levels (negative feedback).

• PTH cells contain a receptor for calcium, coupled to a G

protein.

• calcium ↑→ Gq →PLC→IP3 →calcium inflow↑ ， ER

calcium release↑→ PTH ↓

• Also, vitamin D↑ ， Mg2+↑, P↓ ， somatostatin→PTH↓

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PTH, Calcium & Phosphate

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Vitamin D

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Vitamin D Metabolism

Effects of Active Form of Vit D3• Promotes intestinal absorption of calcium

• promotes bone mobilization (stimulate osteoclasts’ precursor

mature and turnover

→Ca2+↑Pi ↑)mainly

• promotes bone deposition （ stimulate osteoblasts →

osteocalcin↑other protein↑→ deposition ↑ calcification ↑ ）• Has slight effect to increase calcium re-absorption in kidneys

• Works with PTH to cause calcium absorption from bone

• PTH↓

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Proposed Mechanism of Action of 1,25-DihydroxyD3 in Intestine

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Regulation of Vitamin D Metabolism• PTH → 1-hydroxylase activity↑→ production of active form↑

• PTH→ 24-hydroxylase transcription↓→1,24,25 （ OH ） 3D 3↓

• phosphate ↓→ 1-hydroxylase activity↑

• Ca↓→PTH→…………

• 1,25 （ OH ） 2D 3↑→ 1-hydroxylase activity ↓

• 1,25 （ OH ） 2D 3↑→ 24-hydroxylase transcription↑→ 1,24,25 （ O

H ） 3D 3↑

• Growth hormone, prolactin, estrogen, calcitonin→ 1,25 （ OH ） 2D 3↑

• cortisol → 1,25 （ OH ） 2D 3 ↓

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Changes in vitamine D plasma levelHypovitaminosis

• RICKETS (rachitis)– children

• OSTEOMALACIA - adults

▫Attention! – Osteoporosis is decrease of bone

mass (matrix and minerals)

Hypervitaminosis

• Tissue and organs calcification

• Lost of body weight

• Kidney function failure

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Calcitonin

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•Product of parafollicular C cells of the thyroid•32 aa

Calcitonin

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• The target cell for calcitonin is the osteoclast.

--Calcitonin acts via increased cAMP concentrations to inhibit

osteoclast motility and cell shape and inactivates them.

（ 15min ↓70% ， mainly in children but not in adult）--The major effect of calcitonin administration is a rapid fall in

Ca2+ caused by inhibition of bone resorption.

• osteoblastic activity ↑→Ca P deposition ↑ （ 1h）• Ca, P , Mg, Na and Cl resorption in kidney tubules ↓(weak)

Actions of Calcitonin

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Comparison of Calcitonin Effects with PTH Effects

(1) PTH ---- slowly, need several hrs.

CT ----- rapidly, less than 1 hr.

(2) PTH ---- long-term regulation

CT ----- short-term regulation

PS Wang/2004.0

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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).

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Calcitonin• 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.

• May be more important in regulating bone remodeling than in Ca2+ homeostasis.

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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 (high calcium )

gastrin, CCK, glucagon, secretin

increasedcalcitonin

decreased boneresorption 43

Factors affecting bone turnover

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Factors affecting bone turnover • Other hormones

• Glucocorticoids▫ gut - decrease absorption▫ bone - increased re-absorption/decreased formation▫ Kidney-excretion of both calcium and phosphate ↑

• Thyroxine▫ stimulates formation/resorption▫ net resorption▫ Kidney-excretion of calcium↑

• Growth hormone▫ Stimulate bone formation▫ renal calcium excretion ↑▫ gastrointestinal absorption of calcium ↑

• Oestrogen▫ gut - increased absorption▫ bone - decreased re-absorption

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•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.

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47W.F.Ganong:Review of Medical Physiology 2003 20th Ed. fig.21-6 #1441

Factors affecting bone turnover•Local factors• I-LGF 1 (somatomedin C)

▫ increased osteoblast prolifn• TGF

▫ increased osteoblast activity

• IL-1/OAF▫ increased osteoclast activity (myeloma)

• PG’s▫ increased bone turnover (#’s/inflammn)

• BMP▫bone formation

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Factors affecting bone turnover

•Other factors

•Local stresses

•Electrical stimuli

•Environmental

▫temp

▫oxygen levels

▫acid/base balance

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Nutrition and Calcium

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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.

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Nutrition and CalciumSee 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.

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Nutrition and CalciumSee 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.

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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

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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.

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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

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Exercise and Calcium

•Normal bone function requires weight-bearing

exercise

•Total bed-rest causes bone loss and negative

calcium balance

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3. Disorders of calcium metabolism and metabolic bone disease

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Hypercalcaemia

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physiological response of hypercalcaemia

• ↑plasma calcium→↓PTH

• →bone：↓ breakdown of bone; formation of bone

• → gut：↓ formation of calcitrol→less Ca2+uptake from gut

• →kidney：↓ Ca2+absorption→excess Ca2+ lost in urine

• →→↓ plasma 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

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PTHrP; Parathyroid Hormone related Protein

• It is synthesized as 3 isoforms as a result of alternative splicing (139, 141, 173 aa)

• Can activate the PTH receptor• Plays a physiological role in lactation, possibly as a hormone

for the mobilization and/or transfer of calcium to the milk• May be important in fetal development• May play a role in the development of hypercalcemia of

malignancy▫Some lung cancers are associated with hypercalcemia▫Other cancers can be associated with hypercalcemia

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PTHrP; Parathyroid Related Protein

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Symptoms: They are classically summarized by the mnemonic "stones, bones,

abdominal groans and psychic moans”

• "Stones" refers to kidney stones, nephrocalcinosis, and diabetes insipidus (polyuria and polydipsia).

• "Bones" refers to bone-related complications, osteitis fibrosa cystica, which results in pain and sometimes pathological fractures, osteoporosis, osteomalacia, and arthritis.

• “Abdominal Groans” refers to gastric related symptoms such as Abdominal pain, vomiting, constipation and anorexia .

• "Psychic moans” which includes depression, memory loss, psychosis, ataxia, delirium, and coma.

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• Left: Giant Cell Granuloma

• Right: Loss of lamina dura, pathognomonic oral change in

hyperparathyroidism68

Signs

•Proximal muscle weakness

•Signs of Dehydration

•Altered mental state.

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Investigations:• Serum calcium and phosphate: phosphate is low in primary

hyperparathyroidism and some cases of malignancy, normal or

inappropriately high in other causes of hypercalceamia.

• PTH level: high in hyperparathyroidism.

• Radiology (lytic lesions, subperiosteal erosions in the

phalanges).

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Investigation

If PTH is undetectable the following tests should be

done:

• -protein electrophoresis for myeloma.

• -TSH to exclude hyperthyroidism.

• -synacthen test to exclude Addison’s disease.

• -hydrocortisone suppression test, +ve in sarcoidosis, vitamin

D-mediated hypercalceamia and some malignancies.

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Treatment

- Fluids:

- parathyroidectomy

-removing the source of vit D and treating with

glucocorticoids(excess vit D)

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Hypocalcaemia

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physiological response of hypocalcaemia

• ↓ plasma calcium→↑PTH

• → bone：↑ breakdown of bone; formation of bone↓

• → gut：↑ formation of calcitrol→↑Ca2+uptake from gut

• → kidney：↑ Ca2+absorption→↓ Ca2+ lost in urine

• →→↑ plasma calcium

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Sequence of Adjustments to Hypocalcemia

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Causes of Hypocalcemia

Hypoparathyroid

Nonparathyroid PTH Resistance

Postoperative Vitamin D deficiency

Pseudo-hypoparathyroidism

Idiopathic Malabsorption

Post radiation Liver disease

Kidney disease

Vitamin D resistance

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Vitamin D Deficiency• 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 1α-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 77

Rickets

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Vitamin D-Resistant Rickets

• Above: Hypoplastic teeth

• Below: Minimal caries can produce pulpitis; periapical abscesses are thus common

• Lack 1-hydroxylase in kidney

• Rx: Respond well to 1, 25-

dihydroxyD3

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Pseudohypoparathyroidism• Symptoms and signs

▫ Hypocalcemia▫ Hyperphosphatemia▫ Characteristic physical appearance: short stature, round face,

short thick 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• Symptoms begin in children of about 8 years

▫ Tetany and seizures▫ Hypoplasia of dentin or enamel and delay or absence of eruption

occurs in 50% of people with the disorder• Rx: vitamin D and calcium

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Pseudohypoparathyroidism

Elfin facies, short stature, enamel hypoplasia

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Congenital Hypoparathyroidism

• Hypoplasia of the teeth, shortened roots, and retarded eruption82

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.

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Calcium, Bones and Osteoporosis

•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

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Factors that Affect Peak Bone Mass• Gender (M>F), males have greater PBM than females• Race (Blacks >Whites)• Genetics (osteoporosis runs in families and this may be the

predominant factor)

▫Estrogen receptor gene▫Type I collagen gene▫Vitamin D receptor gene

• Gonadal steroids (estrogen and testosterone increase bone mass)

• Growth hormone (increases bone mass)• Calcium intake (supplements work)• Exercise (increases bone mass)

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Vertebrae of 40- vs. 92-year-old women Note the marked loss of trabeculae with preservation of cortex.

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Normal and Osteoporotic Bone

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Sequelae of Osteoporosis

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Osteo-porosis

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Bone Density as a Function of Age

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Treatments (Continued)• 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

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Treatments (Continued)• Raloxifene (Brand name Evista) is a selective estrogen receptor modulator

• Decreases in estrogen levels after menopause lead to increases in bone

resorption and bone loss. Bone is initially lost rapidly because the

compensatory increase in bone formation is inadequate to offset resorptive

losses. This imbalance between resorption and formation is related 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 bone mineral density

(BMD)

• Raloxifene’s biological actions, like those of estrogen, are mediated through

binding to estrogen receptors. This binding results in the modulation of

expression of multiple estrogen-regulated genes in different tissues

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Treatments (Continued)

• 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

D toxicity93

Treatments (Continued)• 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 a fracture

▫ 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 Rx’s Sodium fluoride

Considered a possibility for years Adoption seems unlikely

Strontium ranelate NEJM 350 (2004) 459-468.

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Calcium Content of Foods

• http://www.nal.usda.gov/fnic/foodcomp/Data/SR16/wtrank/wt_rank.html 95

4. Regulation of serum phosphate.

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PHOSPHATES

• 80% bones and teeth

• 10% blood and muscles

• 10% different chemical complexes

• Plasma (ECF) 0.65 – 1.62 mmol/l

• Cell (ICF) 65 mmol/l (including organic P)

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Phosphate Turnover

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