• Calcitonin is a peptide hormone secreted by the thyroid gland.
• Its main effect is to decrease plasma calcium concentration.
• Its actions are generally opposite to PTH.
• However, in humans, calcitonin has a much smaller role than PTH in controlling blood Ca²⁺.
• Calcitonin is synthesized and secreted by parafollicular cells (C cells).
• These cells lie between the thyroid follicles.
• C cells make up only about 0.1% of the human thyroid gland.
• They are remnants of the ultimobranchial glands found in fish, amphibians, reptiles, and birds.
• Calcitonin is a 32–amino acid peptide.
• Its molecular weight is about 3400.

KEY CONCEPT

• Calcitonin → ↓ plasma Ca²⁺.
• PTH → ↑ plasma Ca²⁺.
• Therefore, their calcium effects are generally opposite.
• C cells of thyroid → calcitonin.
• In humans, PTH is much more important than calcitonin for calcium regulation.

Conceptual Examples

• High calcium-control idea:
  Calcitonin acts to lower plasma Ca²⁺.
• Easy comparison:
  PTH → raises Ca²⁺
  Calcitonin → lowers Ca²⁺
• Source:
  Thyroid C cell → calcitonin.

Increased Plasma Calcium Concentration Stimulates Calcitonin Secretion

• The main stimulus for calcitonin secretion is an increase in extracellular Ca²⁺ concentration.
• This is opposite to PTH: ↑ Ca²⁺ → ↑ calcitonin
  ↓ Ca²⁺ → ↑ PTH
• In young animals, about a 10% increase in plasma Ca²⁺ can cause an immediate 2-fold or greater increase in calcitonin secretion (Fig. 80.14).
• This provides another feedback system for controlling plasma Ca²⁺.
• However, this calcitonin feedback system is much weaker than the PTH system.

Calcitonin Decreases Plasma Calcium Concentration

• Calcitonin can rapidly lower blood Ca²⁺, especially in young animals.
• It acts mainly in two ways:
• Immediate effect:
  • Calcitonin decreases osteoclast activity.
  • It may also decrease calcium release through the osteocytic membrane system.
  • Therefore, more calcium remains deposited in bone.
  ↑ Calcitonin → ↓ bone calcium release → ↓ plasma Ca²⁺
• This effect is especially important in young animals because calcium moves rapidly between bone and extracellular fluid.
• Longer effect:
  • Calcitonin decreases formation of new osteoclasts.
  • Fewer osteoclasts eventually lead to fewer osteoblasts, because osteoclastic activity normally stimulates osteoblastic activity.
  • Therefore, over time, both bone resorption and bone deposition decrease.
• Because both processes decrease, calcitonin has little long-term effect on plasma Ca²⁺.
• Its calcium-lowering action is therefore mainly temporary, lasting from a few hours to a few days.
• Calcitonin also has small effects on calcium handling by the kidneys and intestines.
• These effects are generally opposite to PTH but are minor.

Calcitonin Has a Weak Effect on Plasma Calcium Concentration in Adult Humans

• Calcitonin has only a small role in adult human calcium regulation.
• There are two main reasons.
• First, if calcitonin lowers Ca²⁺:
  • ↓ Ca²⁺ strongly stimulates PTH secretion.
  • PTH then opposes and almost overrides the calcitonin effect.
• Even after removal of the thyroid gland, loss of calcitonin does not significantly change long-term blood Ca²⁺ because PTH control is much stronger.
• Second, adults normally have relatively slow rates of bone calcium absorption and deposition.
• Therefore, reducing bone resorption with calcitonin produces only a small change in plasma Ca²⁺.
• Calcitonin has a greater effect in children, because bone remodeling is much faster.
• In children, calcium absorption and deposition may reach 5 g/day or more, about 5–10 times the total calcium present in extracellular fluid.
• Calcitonin can also have a stronger effect in diseases such as Paget disease, where osteoclast activity is greatly increased.

KEY CONCEPT

• ↑ Blood Ca²⁺ → ↑ calcitonin.
• Calcitonin → ↓ osteoclast activity → ↓ bone resorption → ↓ plasma Ca²⁺.
• Calcitonin’s effect is mainly short-term and weak in adults.
• PTH is much more powerful than calcitonin in long-term calcium regulation.
• Calcitonin is more effective when bone turnover is high, such as in children and Paget disease.

Conceptual Examples

• High blood calcium:
  ↑ Ca²⁺ → ↑ calcitonin → ↓ osteoclast activity → less calcium released from bone.
• Calcitonin lowers Ca²⁺:
  ↓ Ca²⁺ → ↑ PTH → PTH opposes the calcitonin effect.
• Adult:
  Slow bone turnover → calcitonin has little effect on plasma calcium.
• Child:
  Rapid bone remodeling → calcitonin has a stronger calcium-lowering effect.

SUMMARY OF CONTROL OF CALCIUM ION CONCENTRATION

• Calcium can enter or leave body fluids very rapidly, sometimes about 0.3 g in 1 hour.
• For example, severe diarrhea can cause loss of several grams of calcium through intestinal secretions and feces.
• Conversely, after a large calcium intake, especially with excess vitamin D, as much as 0.3 g calcium/hour may be absorbed.
• Total calcium in the entire extracellular fluid is only about 1 g.
• Therefore, adding or removing 0.3 g could produce dangerous hypercalcemia or hypocalcemia.
• The body prevents this first by rapid calcium buffering, even before hormonal control becomes fully active.

Buffer Function of the Exchangeable Calcium in Bones—The First Line of Defense

• Bone contains rapidly exchangeable amorphous calcium phosphate salts, mainly CaHPO₄.
• These salts remain in reversible equilibrium with extracellular calcium and phosphate.
• Exchangeable bone calcium represents about 0.5%–1% of total bone calcium, equal to about 5–10 g of calcium.
• When extracellular Ca²⁺ and phosphate rise:
  • Calcium phosphate is rapidly deposited in bone.
• When extracellular Ca²⁺ and phosphate fall:
  • Exchangeable bone salts are rapidly dissolved and released.
• This exchange is very fast because the small amorphous crystals have an enormous total surface area, possibly 1 acre or more.
• About 5% of total blood flow passes through bone each minute.
• Therefore, bone buffering can remove about half of excess extracellular calcium within approximately 70 minutes.
• Mitochondria in many tissues, especially the liver and intestine, also contain exchangeable calcium.
• This represents about 10 g of calcium in the whole body.
• It provides another rapid buffering system for extracellular Ca²⁺.

Hormonal Control of Calcium Ion Concentration—The Second Line of Defense

• While bone is rapidly buffering calcium, PTH and calcitonin also begin to respond.
• Within about 3–5 minutes after blood Ca²⁺ rises:
  • PTH secretion decreases.
  • This activates mechanisms that help lower Ca²⁺ toward normal.
• At the same time:
  • Calcitonin secretion increases.
• In young animals and probably young children, calcitonin rapidly increases calcium deposition in bone.
• Therefore, calcitonin can help correct high Ca²⁺ more rapidly, although its effect is much weaker in adults.
• For long-term calcium excess or deficiency, PTH is much more important than calcitonin.
• During prolonged low calcium intake, PTH can mobilize calcium from bone and maintain plasma Ca²⁺ for 1 year or longer.
• Eventually, however, bone calcium stores can become depleted.
• Therefore, bone acts as a large calcium buffer-reservoir controlled by PTH.
• When bone calcium stores become depleted or saturated, long-term regulation depends mainly on PTH and vitamin D controlling:
  • Calcium absorption from the intestine
  • Calcium excretion by the kidneys

KEY CONCEPT

• Calcium control has two major lines of defense:
  • First line → exchangeable calcium in bone = rapid buffer
  • Second line → PTH and calcitonin = hormonal control
• Bone buffer acts immediately.
• PTH responds within minutes and dominates long-term calcium regulation.
• Calcitonin has mainly a short-term role, especially in young individuals.
• Long-term control depends mainly on: PTH + vitamin D → intestinal calcium absorption + renal calcium excretion

Conceptual Examples

• Sudden rise in Ca²⁺:
  ↑ Blood Ca²⁺ → calcium rapidly deposited in exchangeable bone salts → blood Ca²⁺ buffered toward normal.
• Sudden fall in Ca²⁺:
  ↓ Blood Ca²⁺ → exchangeable calcium dissolves from bone → Ca²⁺ rapidly enters extracellular fluid.
• High Ca²⁺ after a few minutes:
  ↑ Ca²⁺ → ↓ PTH + ↑ calcitonin → calcium falls toward normal.
• Long-term low calcium intake:
  ↑ PTH → calcium mobilized from bone + vitamin D effects increased → plasma Ca²⁺ maintained until bone stores become depleted.

Pathophysiology of Parathyroid Hormone, Vitamin D, and Bone Disease

Hypoparathyroidism

• Hypoparathyroidism occurs when the parathyroid glands secrete too little PTH.
• Low PTH causes:
  • ↓ Osteocytic release of exchangeable calcium
  • Osteoclasts to become almost completely inactive
• Therefore, very little calcium is released from bone into the extracellular fluid.
• As a result, blood calcium decreases.
• However, because calcium and phosphate remain stored in bone, the bones usually remain strong.
• If the parathyroid glands are suddenly removed:
  • Blood calcium falls from about 9.4 mg/dL to 6–7 mg/dL within 2–3 days.
  • Blood phosphate may double.
• When calcium falls this low, tetany develops.
• The laryngeal muscles are especially sensitive to tetanic spasm.
• Laryngeal spasm can obstruct breathing and may cause death if untreated.

Treatment of Hypoparathyroidism With PTH and Vitamin D

• PTH can occasionally be used to treat hypoparathyroidism.
• However, it is usually not preferred because:
  • It is expensive.
  • Its action lasts only a few hours.
  • The body may develop antibodies, making it progressively less effective.
• Most patients are treated with:
  • Large amounts of vitamin D
  • About 1–2 g of calcium
• This treatment can maintain blood calcium within the normal range.
• Sometimes 1,25-dihydroxycholecalciferol (calcitriol) is used instead of inactive vitamin D.
• Calcitriol acts much more rapidly and powerfully.
• However, its strong activity makes excessive vitamin D effects more difficult to avoid.

KEY CONCEPT

• ↓ PTH → ↓ bone calcium release → hypocalcemia + increased phosphate.
• Severe hypocalcemia → tetany.
• Laryngeal tetany can obstruct respiration and become fatal.
• Bones generally remain strong because bone resorption is reduced.
• Main treatment: Vitamin D + calcium → maintain normal blood Ca²⁺

Conceptual Examples

• After parathyroid removal:
  ↓ PTH → ↓ calcium release from bone → blood Ca²⁺ falls to 6–7 mg/dL → tetany.
• Phosphate:
  ↓ PTH → less phosphate excretion and less release from bone → blood phosphate may rise markedly.
• Dangerous tetany:
  Severe hypocalcemia → laryngeal muscle spasm → airway obstruction.
• Treatment:
  Vitamin D + calcium → ↑ available calcium → blood Ca²⁺ maintained near normal.

Primary Hyperparathyroidism

• Primary hyperparathyroidism occurs when the parathyroid glands secrete excess PTH inappropriately.
• The usual cause is a parathyroid adenoma, a noncancerous tumor of one parathyroid gland.
• It occurs about 3–4 times more often in women than in men or children.
• Pregnancy and lactation stimulate the parathyroid glands and may favor development of an adenoma.
• After menopause, estrogen deficiency increases bone resorption, which can make the bone effects of hyperparathyroidism more obvious.
• Although it can occur at any age, most cases occur between about 50–65 years.
• Severe excess PTH causes marked osteoclast activity.
• Therefore:
  • Blood Ca²⁺ increases
  • Blood phosphate usually decreases because the kidneys excrete more phosphate.

Bone Disease in Hyperparathyroidism

• In mild disease, increased osteoblast activity may compensate for increased osteoclast bone resorption.
• In severe disease, bone resorption becomes much greater than bone deposition.
• As a result, bones become severely weakened and may even be largely destroyed.
• A fracture may be the first reason a patient seeks medical attention.
• X-rays may show:
  • Extensive bone decalcification
  • Large punched-out cystic areas
  • Giant-cell osteoclast collections
• Weak bones may fracture after only minor trauma, especially where cysts are present.
• This cystic bone disease is called osteitis fibrosa cystica.
• Osteoblast activity also increases in an attempt to replace lost bone.
• Active osteoblasts release large amounts of alkaline phosphatase.
• Therefore, high plasma alkaline phosphatase is an important finding in hyperparathyroidism.

Effects of Hypercalcemia in Hyperparathyroidism

• Plasma calcium may rise to about 12–15 mg/dL, and occasionally even higher.
• Hypercalcemia can cause:
  • Depression of the central and peripheral nervous systems
  • Muscle weakness
  • Constipation
  • Abdominal pain
  • Peptic ulcer
  • Loss of appetite
  • Reduced relaxation of the heart during diastole

Parathyroid Poisoning and Metastatic Calcification

• Rarely, extremely high PTH secretion causes a rapid and severe rise in blood calcium.
• In this extreme situation, blood phosphate may also rise instead of falling.
• This occurs because the kidneys may be unable to excrete all the phosphate released from bone.
• High calcium + high phosphate causes the body fluids to become supersaturated.
• Calcium phosphate (CaHPO₄) crystals may then deposit in:
  • Lung alveoli
  • Kidney tubules
  • Thyroid gland
  • Acid-producing gastric mucosa
  • Arterial walls
• This widespread abnormal deposition is called metastatic calcification.
• It can develop within only a few days.
• Parathyroid poisoning usually becomes dangerous when blood calcium rises above about 17 mg/dL.
• If severe hypercalcemia occurs together with high phosphate, death may occur within a few days.

KEY CONCEPT

• Primary hyperparathyroidism → excess PTH, usually from parathyroid adenoma.
• ↑ PTH → ↑ osteoclast activity → ↑ blood Ca²⁺ + usually ↓ blood phosphate.
• Severe disease → bone loss → osteitis fibrosa cystica + fractures.
• ↑ Osteoblast activity → ↑ alkaline phosphatase.
• Extreme PTH excess → very high Ca²⁺ + phosphate → metastatic calcification.
• Ca²⁺ >17 mg/dL → risk of parathyroid poisoning and death.

Conceptual Examples

• Typical primary hyperparathyroidism:
  Parathyroid adenoma → ↑ PTH → ↑ bone resorption → hypercalcemia + low phosphate.
• Bone disease:
  Persistent ↑ PTH → osteoclast activity exceeds osteoblast repair → weak bones + fractures.
• Laboratory clue:
  Bone repair attempts increase osteoblast activity → ↑ plasma alkaline phosphatase.
• Extreme disease:
  Very high PTH → ↑ Ca²⁺ + ↑ phosphate → calcium phosphate deposits in tissues → metastatic calcification.

Formation of Kidney Stones in Hyperparathyroidism

• Many patients with mild hyperparathyroidism have little obvious bone disease or other symptoms.
• However, they have a strong tendency to develop kidney stones.
• Excess PTH causes more calcium and phosphate to enter the blood from:
  • Increased intestinal absorption
  • Increased release from bone
• These excess minerals must eventually be excreted by the kidneys.
• Therefore, urinary concentrations of calcium and phosphate increase.
• High urinary calcium and phosphate can precipitate as crystals and form calcium phosphate stones.
• Calcium oxalate stones can also form because high calcium allows even normal amounts of oxalate to precipitate with calcium.
• Kidney stones form more easily in alkaline urine because alkalinity decreases the solubility of many renal stones.
• Therefore, the text notes that acidotic diets and acidic drugs have been used to treat renal calculi.

Secondary Hyperparathyroidism

• Secondary hyperparathyroidism occurs when PTH rises as a compensatory response to hypocalcemia.
• The parathyroid gland itself is not initially abnormal.
• This differs from primary hyperparathyroidism: Primary hyperparathyroidism → ↑ PTH + hypercalcemia
  Secondary hyperparathyroidism → hypocalcemia → compensatory ↑ PTH
• Secondary hyperparathyroidism can result from:
  • Vitamin D deficiency
  • Chronic kidney disease
• In chronic kidney disease, damaged kidneys cannot produce enough active vitamin D, 1,25-dihydroxycholecalciferol (calcitriol).
• Reduced vitamin D activity causes inadequate bone mineralization, called osteomalacia.
• The associated low calcium stimulates increased PTH secretion.
• High PTH then increases bone resorption.

KEY CONCEPT

• Hyperparathyroidism → ↑ urinary calcium and phosphate → kidney stone formation.
• Common stones include:
  • Calcium phosphate
  • Calcium oxalate
• Secondary hyperparathyroidism = low Ca²⁺ stimulates compensatory ↑ PTH.
• Common causes:
  • Vitamin D deficiency
  • Chronic renal disease → ↓ calcitriol
• Easy comparison: Primary → PTH problem first → hypercalcemia
  Secondary → hypocalcemia first → compensatory ↑ PTH

Conceptual Examples

• Kidney stone:
  ↑ PTH → ↑ calcium mobilization → ↑ urinary Ca²⁺ → calcium-containing stones form.
• Chronic kidney disease:
  Damaged kidney → ↓ calcitriol → ↓ calcium availability → ↑ PTH.
• Vitamin D deficiency:
  ↓ Vitamin D → poor bone mineralization + ↓ Ca²⁺ → secondary hyperparathyroidism.

Rickets Caused By Vitamin D Deficiency

• Rickets occurs mainly in children and usually results from vitamin D deficiency, causing inadequate calcium or phosphate in the extracellular fluid.
• Sunlight helps prevent rickets because: 7-dehydrocholesterol in skin + ultraviolet light → vitamin D₃
• Vitamin D₃ then increases intestinal absorption of calcium and phosphate.
• Children who stay indoors during winter may not receive enough vitamin D unless it is supplied in the diet.
• Rickets may become more noticeable in the spring because:
  • Vitamin D stored from the previous summer can support the body during early winter.
  • Calcium and phosphate can initially be mobilized from bone, delaying obvious signs of deficiency.

Plasma Concentrations of Calcium and Phosphate Decrease in Rickets

• In rickets, plasma calcium falls only slightly, whereas plasma phosphate falls markedly.
• When calcium begins to fall, the parathyroid glands increase PTH secretion.
• PTH increases bone resorption, helping maintain blood calcium near normal.
• However, PTH also increases phosphate excretion in urine.
• Therefore: Vitamin D deficiency → ↓ Ca²⁺ absorption → ↑ PTH → Ca²⁺ partly maintained but phosphate falls greatly

Rickets Weakens the Bones

• Prolonged rickets causes a large compensatory increase in PTH.
• High PTH causes increased osteoclastic bone resorption.
• The bones therefore become progressively weak.
• Increased stress on weakened bone also stimulates osteoblast activity.
• Osteoblasts produce large amounts of osteoid.
• However, this osteoid cannot calcify properly because there is insufficient calcium and phosphate.
• Therefore, old bone is gradually replaced by uncalcified, weak osteoid.

Tetany in Rickets

• Tetany is uncommon in the early stages because increased PTH maintains blood calcium by increasing bone resorption.
• Eventually, if bone calcium stores become depleted, blood calcium may fall rapidly.
• When blood calcium falls below about 7 mg/dL, tetany may occur.
• Severe tetany can cause respiratory muscle spasm and death.
• Intravenous calcium can relieve the tetany immediately.

Treatment of Rickets

• Treatment requires adequate:
  • Calcium
  • Phosphate
  • Vitamin D
• Vitamin D is especially important because without it, only small amounts of calcium and phosphate are absorbed from the intestine.

KEY CONCEPT

• Vitamin D deficiency → ↓ intestinal Ca²⁺ + phosphate absorption → rickets.
• ↑ PTH keeps Ca²⁺ near normal but causes more phosphate loss in urine.
• Therefore, in rickets: Ca²⁺ = slightly decreased
  Phosphate = markedly decreased
• ↓ Ca²⁺ + ↓ phosphate → osteoid cannot mineralize → soft, weak bones.
• Severe late hypocalcemia → tetany.

Conceptual Examples

• Vitamin D deficiency:
  ↓ Vitamin D → ↓ Ca²⁺ and phosphate absorption → poor bone mineralization.
• Why phosphate falls more:
  ↓ Ca²⁺ → ↑ PTH → kidney loses more phosphate → marked hypophosphatemia.
• Weak bone:
  Osteoblast makes osteoid → not enough Ca²⁺ and phosphate → osteoid remains uncalcified.
• Severe rickets:
  Bone calcium stores exhausted → Ca²⁺ < 7 mg/dL → tetany and possible respiratory spasm.

Osteomalacia—“Adult Rickets”

• Osteomalacia is essentially rickets in adults.
• Adults usually do not develop severe vitamin D or calcium deficiency because they do not need large amounts of calcium for rapid bone growth.
• However, severe deficiency can occur in steatorrhea, where the intestine fails to absorb fat properly.
• Because vitamin D is fat-soluble, poor fat absorption causes vitamin D to be lost in the feces.
• Calcium can also combine with fat to form insoluble soaps, so calcium absorption decreases.
• Therefore: Steatorrhea → ↓ vitamin D absorption + ↓ calcium absorption → poor Ca²⁺/phosphate availability → osteomalacia
• In adults, osteomalacia rarely progresses to tetany.
• However, it can cause severe bone weakness and disability.

Osteomalacia and Rickets Caused By Kidney Disease

• Renal rickets is osteomalacia caused by prolonged kidney damage.
• Damaged kidneys cannot adequately form 1,25-dihydroxycholecalciferol (calcitriol), the active form of vitamin D.
• Therefore, severe renal disease can cause poor bone mineralization.
• This problem may be especially severe in patients with destroyed or removed kidneys who require hemodialysis.
• Another renal cause is congenital hypophosphatemia.
• In this disorder, renal tubules have reduced ability to reabsorb phosphate.
• Therefore, excessive phosphate is lost in urine and bone mineralization becomes defective.
• This form is called vitamin D–resistant rickets.
• It requires treatment with phosphate compounds rather than calcium and vitamin D.

KEY CONCEPT

• Osteomalacia = adult form of poor bone mineralization.
• Steatorrhea → ↓ vitamin D + ↓ calcium absorption → osteomalacia.
• Kidney damage → ↓ calcitriol → renal osteomalacia/rickets.
• Congenital renal phosphate wasting → hypophosphatemia → vitamin D–resistant rickets.
• Vitamin D–resistant rickets is treated mainly with phosphate.

Conceptual Examples

• Steatorrhea:
  Fat not absorbed → vitamin D lost + calcium forms insoluble soaps → poor bone mineralization.
• Chronic kidney disease:
  Damaged kidney → ↓ calcitriol → ↓ effective vitamin D action → osteomalacia.
• Congenital phosphate loss:
  ↓ Renal phosphate reabsorption → ↑ phosphate loss in urine → weak mineralization despite vitamin D.

Osteoporosis—Decreased Bone Matrix

• Osteoporosis is the most common bone disease in adults, especially in old age.
• It differs from rickets and osteomalacia because the main problem is decreased organic bone matrix, not poor mineralization.
• In most cases, osteoblast activity is reduced, so less osteoid is formed.
• In some cases, such as hyperparathyroidism, excessive osteoclast activity causes the bone loss.
• Important causes of osteoporosis include:
  • Lack of physical stress / inactivity → less stimulation for bone formation.
  • Malnutrition → not enough protein available to form bone matrix.
  • Vitamin C deficiency → reduced formation of intercellular substances and osteoid by osteoblasts.
  • Postmenopausal estrogen deficiency:
    • ↑ osteoclast number and activity
    • ↑ osteoblast apoptosis
    • Therefore, bone loss increases.
  • Old age:
    • ↓ Growth hormone and other growth factors
    • ↓ Protein-building functions
    • Therefore, less bone matrix is deposited.
  • Cushing syndrome:
    • Excess glucocorticoids → ↓ protein deposition
    • ↑ protein breakdown
    • ↓ osteoblast activity
    • Therefore, bone matrix decreases.
• Thus, many disorders that reduce protein formation or increase protein breakdown can lead to osteoporosis.

KEY CONCEPT

• Osteoporosis = decreased amount of bone matrix.
• Osteomalacia/rickets = poor mineralization of bone.
• Main mechanism in osteoporosis: ↓ Osteoblast activity and/or ↑ osteoclast activity → ↓ bone mass
• Major causes include:
  • Inactivity
  • Malnutrition
  • Vitamin C deficiency
  • Estrogen deficiency
  • Old age
  • Cushing syndrome

Conceptual Examples

• Postmenopause:
  ↓ Estrogen → ↑ osteoclast activity → more bone loss.
• Inactivity:
  ↓ Bone stress → ↓ osteoblast stimulation → less bone formation.
• Cushing syndrome:
  ↑ Glucocorticoids → ↓ protein formation + ↓ osteoblast activity → decreased bone matrix.
• Easy comparison:
  Osteoporosis = too little bone matrix.
  Osteomalacia = bone matrix present but poorly mineralized.

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