Guyton and Hall Physiology Chapter 80 - Parathyroid Hormone

Calcium and Phosphate Metabolism Overview

• Closely connected with bone and tooth formation and regulation by vitamin D, parathyroid hormone (PTH), and calcitonin.
• Extracellular calcium ion concentration depends on calcium absorption from the intestine, renal excretion, bone uptake/release, all hormone-regulated.
• Phosphate homeostasis is associated with calcium homeostasis.

Calcium and Phosphate Regulation in Extracellular Fluid and Plasma

• Extracellular fluid calcium is tightly regulated, seldom varying more than a few percent from 9.4 mg/dL (2.4 mmol/L).
• Regulation is essential for muscle contraction, blood clotting, nerve impulse transmission, etc.
• High calcium (hypercalcemia) causes nervous system depression; low calcium (hypocalcemia) causes excitation.
• Only 0.1% of total body calcium is extracellular, 1% in cells, the rest is stored in bones, serving as reservoirs.
• About 85% of body phosphate stored in bones, 14-15% in cells, less than 1% in extracellular fluid.
• Phosphate serves important functions and is regulated by factors that also regulate calcium.

Calcium in Plasma and Interstitial Fluid

• Exists in three forms: (1) 41% (1 mmol/L) bound to plasma proteins (non-diffusible), (2) 9% (0.2 mmol/L) complexed with anions (diffusible, non-ionized), (3) 50% ionized (diffusible).
• Normal calcium ion concentration in plasma and interstitial fluids is about 1.2 mmol/L (2.4 mEq/L), half the total plasma calcium concentration.
• Ionic calcium is crucial for heart function, nervous system activity, and bone formation.

Inorganic Phosphate in Extracellular Fluids

• Mainly exists as HPO4= and H2PO4-.
• HPO4= concentration is about 1.05 mmol/L, H2PO4- is about 0.26 mmol/L.
• Total phosphate level rises, increasing both forms.
• Acidic pH increases H2PO4-, alkaline pH increases HPO4=.
• Phosphate is expressed as milligrams of phosphorus per deciliter (mg/dl).
• Average total inorganic phosphorus is about 4 mg/dl (3-4 mg/dl in adults, 4-5 mg/dl in children).

Nonbone Physiological Effects of Altered Calcium and Phosphate Concentrations

• Altering phosphate levels has minor immediate effects.
• Even minor changes in calcium ion can cause extreme immediate effects.
• Chronic hypo states greatly decrease bone mineralization.

Hypocalcemia and Tetany

• Decreased calcium ion increases nerve excitability because neuronal membrane permeability to Na+ increases.
• Plasma calcium reduction of 50% can cause spontaneous nerve discharge and tetanic muscle contraction.
• Tetany occurs at 6 mg/dl (35% below normal); lethal is around 4 mg/dl for Calcium.
• Extreme hypo states can cause heart dilation, enzyme activity changes, increased membrane permeability, impaired clotting.

Hypercalcemia and Depressed Muscle Activity

• Elevated calcium causes nervous system depression, sluggish reflexes.
• Increased calcium decreases the QT interval of the heart and causes appetite loss and constipation.
• Depressive effects appear above 12 mg/dl, and are marked above 15 mg/dl.
• Above 17 mg/dl, calcium phosphate crystals may precipitate, which leads to parathyroid poisoning.

Absorption and Excretion of Calcium and Phosphate

• Usual intake is approximately 1000 mg/day of both calcium and phosphorus.
• Divalent ions like calcium are poorly absorbed in the intestines; vitamin D promotes absorption.
• About 35% (350 mg/day) of calcium is absorbed; the remainder is excreted in feces.
• 250 mg/day of calcium enters intestines via gastrointestinal juices.
• Approximately 90% (900 mg/day) of calcium intake is excreted in feces.
• Intestinal absorption of phosphate is easy.
• Except for what is not absorbed in combination with Calcium, nearly all dietary phosphate is absorbed into the blood and excreted in the urine.

Renal Excretion of Calcium and Phosphate

• Approximately 10% (100 mg/day) of ingested calcium excreted in urine.
• About 41% of plasma calcium is bound to plasma proteins (non-filterable).
• The remainder combined with anions (9%) or ionized (50%) and is filtered into renal tubules.
• Renal tubules reabsorb 99% of filtered calcium; about 100 mg/day excreted in urine.
• Approximately 90% of glomerular filtrate calcium is reabsorbed in proximal tubules, loops of Henle, and early distal tubules.
• Reabsorption of remaining 10% in the late distal tubules and early collecting ducts varies depending on blood calcium ion concentration.
• With low Calcium, there is a great amount of reabsorption and little is lost in the urine.
• With high Calcium, minute concentration rise increases Calcium excretion markedly.
• PTH controls distal nephron reabsorption, thus controlling calcium excretion rate.
• Renal phosphate excretion is controlled via overflow mechanism.
• Below about 1 mmol/L phosphate plasma, all phosphate in glomerular filtrate reabsorbed, none lost in urine.
• Above critical concentration, phosphate loss rate is directly proportional to rise.
• Kidneys regulate phosphate concentration via phosphate excretion rate per plasma concentration.
• PTH can greatly increase kidney phosphate excretion, controlling phosphate and calcium.

Bone and Its Relationship to Extracellular Calcium and Phosphate

• Two types of bony tissue: cortical (compact) and trabecular (spongy) bone.
• Cortical bone forms the hard, dense outer layer, about 80% of total bone mass.
• Trabecular bone accounts for about 20% and is found at long bone ends, near joints, and in vertebrae.
• Bone consists of lattice-shaped units, bony spicules(trabeculae) that form an irregular meshwork.
• Spaces between trabeculae filled with red bone marrow (hematopoiesis).
• Synthesis, resorption (bone turnover rate) higher for trabecular bone than cortical bone.
• Cortical bone has a strong organic matrix strengthened by deposits of calcium salts.
• Average cortical bone is about 30% matrix and 70% salts by weight; newly formed bone may have matrix > salts.

Organic Matrix of Bone

• Contains 90-95% collagen fibers and ground substance.
• Collagen fibers extend along lines of tensional force, bone provides tensile strength.
• Ground substance is extracellular fluid plus proteoglycans (chondroitin sulfate, hyaluronic acid).
• Proteoglycans help control calcium salt deposition and bone repair.

Bone Salts

• The crystalline salts are principally calcium and phosphate.
• Major crystalline salt is hydroxyapatite (Ca10(PO4)6(OH)2).
• The hydroxyapatite crystal is shaped like a long, flat plate.
• Calcium to phosphorus ratio varies (1.3-2.0 weight basis).
• Magnesium, sodium, potassium, and carbonate ions are among them, but no distinct crystals formed.
• Ability of ions to conjugate to bone crystals extends to ions foreign to bone (strontium, uranium, plutonium, lead, gold, etc.).
• Deposition of radioactive substances can cause bone tissue irradiation, osteogenic.

Tensile and Compressional Strength of Bone

• Each collagen fiber of cortical (compact) bone has repeating segments every 640 Å.
• Hydroxyapatite crystals lie adjacent to fiber segments and are bound tightly.
• Intimate bonding prevents shear.
• Segments of adjacent collagen fibers overlap.
• Collagen fibers (like tendons) provide tensile strength, whereas calcium salts provide compressional strength.
• Combined properties provide bony structure with extreme strength.

Precipitation and Absorption

• Calcium and phosphate ions are significantly greater to cause hydroxyapatite precipitation.
• Inhibitors prevent precipitation in tissues; one is pyrophosphate
• Hydroxyapatite crystals dont precipitate, except for in the bones.

Mechanism of Bone Calcification

• Initial stage: osteoblasts secrete collagen molecules (collagen monomers), ground substance (proteoglycans).
• Collagen monomers polymerize to form collagen fibers; tissue becomes osteoid which is cartilage-like with a ready to precipitate calcium salts.
• As osteoid forms, osteoblasts become trapped and quiescent (osteocytes).
• Within days, calcium salts precipitate on collagen fibers as minute nidi that multiply and grow into hydroxyapatite crystals.
• Initial salts deposited are amorphous such as CaHPO4 × 2H2O, Ca3(PO4)2 × 3H2O which turns into hydroxyapatite crystals in weeks/months through substitution and addition of atoms, or reabsorption/reprecipitation.
• A few percent may remain permanently in the amorphous form.
• Process appears to depend upon pyrophosphate which is inhibited via hydroxyapatite crystallization which is regulated by at least three molecules.
• One is a substance called tissue-nonspecific alkaline phosphatase (TNAP), breaks down pyro to enable bone calcification to occur.
• TNAP secreted by osteoblasts to neutralize pyro; collagen fiber affinity causes hydroxyapatite crystallization.

Osteoblast Regulation

• Mice with TNAP deficiency have soft, uncalcified bones because of high pyro levels.
• Osteoblasts secrete (1) nucleotide pyrophosphatase phosphodiesterase 1 (NPP1): produces pyrophosphate, (2) ankylosis protein (ANK): transports pyrophosphate from interior to surface.
• Deficiencies of NPP1/ANK cause decreased pyro, excessive bone calcification, bone spurs, spine calcification of tendons and ligaments, ankylosing spondylitis.

Calcium Precipitation in Nonosseous Tissues Under Abnormal Conditions

• Calcium salts usually do not precipitate in normal tissues besides bone, under abnormal conditions, they can precipitate.
• Calcium salts precipitate in arterial walls during arteriosclerosis and form bonelike tubes.
• Calcium salts deposit in degenerating tissues/blood clots.
• Inhibitor factors disappear from tissues, allowing precipitation.

Calcium Exchange Between Bone and Extracellular Fluid

• If soluble calcium salts are injected, calcium immediately rises to high levels.
• Within 30-60 minutes, calcium returns to normal due to bone.
• Large amounts of calcium ions are removed, concentration returns to normal in 30 minutes to about 1 hour.
• Exchangeable calcium is mostly in bone (0.4-1% of total bone calcium).
• Exchangeable provides rapid buffering to keep calcium from rising/falling excessively.

Bone and Extracellular Deposition

• Bone is continually deposited by osteoblasts, resorbed by osteoclasts.
• Osteoblasts on outer surfaces of bones/in bone trabecular cavities.
• Small osteoblastic activity occurs continually in all living bones, new bone being performed constantly.

Resorption of Bone

• Bone is continually resorbed by osteoclasts, large cells with many nuclei.
• PTH controls resorptive ability of bone’s osteoclasts.
• Histologically, bone absorption occurs immediately adjacent to osteoclasts.
• Osteoclasts send out villus-like projections to bone, forming ruffled border.
• Villi secrete (1) proteolytic enzymes to dissolve organic matrix and (2) acids (citric, lactic acid) to dissolve salts.
• Minute particles of matrix/crystals are imbibed via phagocytosis and dissolved & released.
• PTH stimulates osteoclast activity via indirect mechanism.
• The matrix is the bone-resorbing osteoclast cells, they do not have HTN receptors.
• There are two osteoblasts proteins, receptor activity and nuclear factor kB ligand (RANKL) and which are both colony-stimulating factor.
• Protein stimulates the osteoblasts synthesis of RANKL, which is called (OPGL).
• R/RANK bind to receptors (rank) causes differentiated into mature osteoclasts.
• The OPGs produce osteoblastic is a factor also called osteoclastogenesis, cytokines that prevent bone absorption.

Equilibrium and Remodeling

• Except when bones are growing, the decomposition has a normal equality so total mass becomes constant.
• Osteoclasts exist in the same masses, usually in the bone.
• Development occurs it usually tears at then for about 3 weeks.
• Cannulial tunnel ranging from .2 mm for the diameter and the length is several.
• With time the osteoclasts disappear, tunnel is covered up by osteoblasts.
• Consists of concentric circles (lamellae ) tunnel filled with deposits of new bone.
• New deposits seize while the blood encroach the suppyling tunnel.

Value of Continued Bone Remodeling

• Consisted deposition several important functions.
• 1st to just strength and proportion
• Bones thick when objects are heavy loads.
• 2nd shape can be rearrange supporting force
• 3rd new matrix needs
• Children have little brittle bones/rates are slow
• Elderly/ slow

Rate of Bone Deposition by Stress

• Compression load proportions bones must carry
• Bones athletes way bigger, opposite leg heavier
• Walks with cast is thinner

Repair of Fracture Activates Osteoblasts

• Activate periosteal fully involved in the break
• There are immense numbers of new stem cells.
• Osteoblastic creates new material shortly with calcium salt deposits
• Callus
• Orthopedic surgeons speed fracture, mechanical holding with accelerence bone break

Vitamine D

• Potent calcium from intestine
• Bone Deposition
• Bone Resportipn
• Actuel causational efects
• Must be first converted to the substance 1,25-didroxyy cholecalciferol

Cholecalciferol and vitamin families

• The skin forms cholecalciferol
• Resulting with 7dehydrocho lestoral
• Additional Vitamin is identify by Cholesteral

###Liver

• The 25hydrozichocaleciferol first conversion
• Feedback inhibition
• precisely regulates

Factors/ effects.

• The proximal conversion in the kidnes
• Calcium has control
• Calcium stops conversion
• PTH
• PTH converts
• Lavk of vitamin