Parathyroid Gland, Calcitonin and Vitamin D

Introduction

Calcium balance and bone strength depend on the coordinated actions of parathyroid hormone, calcitonin, and vitamin D. These regulators control plasma calcium, phosphate homeostasis, bone resorption, and proper mineralization, ensuring normal skeletal growth and maintenance.

• Parathyroid hormone, calcitonin, and vitamin D3 are the major regulators of calcium and phosphorus metabolism.
• They maintain plasma mineral balance and support normal bone growth, remodeling, and mineralization. Their functions are commonly studied together in physiology.

Parathyroid Gland

• The parathyroid glands secrete parathyroid hormone, an essential regulator of calcium and phosphate metabolism.
• Parathyroid hormone increases plasma calcium concentration and lowers plasma phosphate concentration.

Physiological Anatomy

• Most individuals have four parathyroid glands. They are usually located on the posterior surface of the thyroid gland in the neck, near its upper and lower poles. These glands develop from the third and fourth pharyngeal pouches during fetal life.
• The combined weight of all glands is about 200 milligrams. Their arterial supply is mainly derived from branches of the thyroid arteries.

Cell Types

The parathyroid glands contain two principal cell types: chief cells and oxyphil cells.

Chief Cells

• Chief cells are the predominant functional cells and are present throughout life. They contain a prominent Golgi apparatus, abundant endoplasmic reticulum, and secretory vesicles.
• Chief cells synthesize and secrete parathyroid hormone, which regulates calcium and phosphate balance.

Oxyphil Cells

• Oxyphil cells are fewer in number than chief cells. They usually appear around puberty and increase with advancing age. These cells contain numerous eosinophilic granular mitochondria-rich cytoplasm.
• Oxyphil cells generally have minimal secretory function, but occasionally may produce parathyroid hormone.

Parathyroid Hormone (PTH)

Structure

• Parathyroid hormone is a single-chain polypeptide composed of 84 amino acids. Its molecular weight is approximately 9,500 daltons.
• The N-terminal region contains the major biological activity, especially calcium regulation.
• The C-terminal region has comparatively limited direct physiological activity.

Synthesis, Secretion and Metabolism

• Parathyroid hormone is a peptide hormone synthesized by chief cells of the parathyroid gland. It is initially produced as preproparathyroid hormone, a precursor containing 115 amino acids.
• In the rough endoplasmic reticulum, the signal peptide of 25 amino acids is removed to form proparathyroid hormone.
• Further processing in the Golgi apparatus removes additional amino acids to produce mature parathyroid hormone, which contains 84 amino acids.
• The mature hormone is packaged into secretory granules and stored until release.

Regulation of Secretion

• The most important regulator of parathyroid hormone secretion is the concentration of ionized calcium in plasma.
• Plasma calcium and parathyroid hormone show an inverse relationship.
• When ionized calcium rises, hormone secretion decreases.
• When calcium falls, hormone secretion increases rapidly to restore calcium balance.
• Approximately 50 percent of total plasma calcium is present in ionized form, which is the biologically active fraction.

Plasma Calcium Level

• Chief cells contain calcium-sensing receptors on their cell membrane. These receptors are G protein-coupled receptors that detect extracellular calcium concentration.
• Increased calcium activates phospholipase C and generates inositol trisphosphate and diacylglycerol. These intracellular signals raise cytosolic calcium and activate protein kinase C.
• The final effect is suppression of parathyroid hormone release.

Vitamin D

• Active vitamin D suppresses parathyroid hormone synthesis. It decreases transcription of preproparathyroid hormone messenger ribonucleic acid and reduces glandular hyperactivity.

Other Factors

• Elevated phosphate may indirectly stimulate parathyroid hormone secretion by lowering free calcium concentration and reducing active vitamin D formation.
• Mild reduction in magnesium can stimulate secretion, whereas severe magnesium deficiency may impair hormone release.
• Beta-adrenergic agonists, dopamine, and histamine acting through H2 receptors may enhance secretion.
• Prostaglandins and alpha-adrenergic agonists may inhibit secretion in some settings.

Metabolism of PTH

• Normal plasma parathyroid hormone concentration is approximately 10–60 picograms per milliliter, depending on assay method.
• The hormone has a short half-life of about 2 to 5 minutes in modern estimates because it is rapidly metabolized.
• The liver and kidneys are major sites of degradation and clearance.
• Circulating fragments, especially C-terminal fragments, are removed mainly by the kidneys.

• Synthetic parathyroid hormone fragments, especially amino-terminal forms, retain biological activity and may be used therapeutically in selected bone disorders.

Mechanism of Action

PTH Receptors

• Parathyroid hormone acts through specific membrane receptors present in target tissues such as bone and kidney.
• Three receptor types have been described: type 1, type 2, and carboxy-terminal receptors.H6:

Type 1 Receptor (PTH 1R)

• Type 1 receptor (PTH1R) binds parathyroid hormone and parathyroid hormone-related protein. It is the principal receptor responsible for regulation of plasma calcium and phosphate balance.

Type 2 Receptors (PTH 2R)

• Type 2 receptor (PTH2R) binds parathyroid hormone but has little affinity for parathyroid hormone-related protein. It is found mainly in the brain, pancreas, and placenta.

Type 3 Receptor (CPTH)

• Carboxy-terminal receptors interact with C-terminal hormone fragments and may have modulatory roles.

G Proteins for PTH

• Type 1 and type 2 receptors are coupled to Gs and Gq proteins.
• Hormone binding activates adenylate cyclase and phospholipase C pathways simultaneously.
• Activation of adenylate cyclase increases cyclic adenosine monophosphate levels. This activates protein kinase A, which phosphorylates intracellular proteins and modifies ion transport.
• Phospholipase C generates inositol trisphosphate and diacylglycerol.
• Inositol trisphosphate releases intracellular calcium stores.
• Diacylglycerol activates protein kinase C, producing additional cellular responses.

Physiological Actions

• The primary effect of parathyroid hormone is to increase plasma calcium and decrease plasma phosphate concentration. It acts mainly on the kidneys, bone, and intestine.
• The hormone increases movement of calcium into the extracellular fluid and blood.
• Bone resorption and intestinal absorption may increase phosphate entry into plasma.
• However, enhanced renal phosphate excretion exceeds this effect, so plasma phosphate falls overall.

Actions on Kidney

• Parathyroid hormone receptors are present on renal tubular cells. It increases calcium reabsorption, especially in the distal nephron, reducing urinary calcium loss.
• It decreases phosphate reabsorption in the proximal tubule, causing phosphaturia.
• It stimulates formation of 1,25-dihydroxyvitamin D, which enhances intestinal calcium absorption.

Increased reabsorption of calcium

• Normally, filtered calcium is reabsorbed mainly in the proximal tubule, thick ascending limb, and distal tubule.
• Only about 1–2 percent of filtered calcium is usually excreted in urine.
• Parathyroid hormone increases renal calcium reabsorption, especially in the distal tubule and thick ascending limb of the loop of Henle. As a result, urinary calcium loss falls and plasma calcium rises. This renal effect can occur rapidly, often within minutes.
• The hormone also stimulates production of 1,25-dihydroxyvitamin D, which further supports calcium handling.

Decreased reabsorption of phosphate

• Parathyroid hormone decreases phosphate reabsorption mainly in the proximal tubule. This causes phosphaturia and lowers plasma phosphate concentration.
• Reduced phosphate helps prevent calcium-phosphate crystal precipitation in tissues.

Stimulation of 1, 25-dihydroxycholecalciferol formation

• In the proximal renal tubule, parathyroid hormone stimulates the enzyme 1-alpha-hydroxylase in mitochondria. This converts 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D, the active form of vitamin D.
• Active vitamin D increases intestinal calcium and phosphate absorption. It also enhances renal calcium reabsorption and supports bone mineral regulation.

Actions on Bone

• Parathyroid hormone acts indirectly on osteoclasts through receptors on osteoblast lineage cells. It increases expression of receptor activator of nuclear factor kappa-B ligand, which promotes osteoclast formation and activity.
• Although bone formation and resorption are both influenced, the dominant continuous effect is bone resorption.
• Calcium and phosphate are released from bone into extracellular fluid and plasma.
• Sustained elevation of parathyroid hormone increases the number and size of osteoclasts. It also promotes differentiation of monocyte-macrophage precursors into mature osteoclasts.
• Osteoclasts dissolve mineral and degrade organic matrix using acid and proteolytic enzymes.
• Bone resorption releases calcium, phosphate, hydroxyproline, and hydroxylysine.
• Increased urinary hydroxyproline may indicate enhanced bone breakdown.

• Parathyroid hormone can rapidly increase calcium transfer from bone fluid to extracellular fluid. This occurs through osteocyte-osteoblast membrane systems and does not initially require major matrix destruction. It helps correct acute hypocalcemia.
• High continuous levels of parathyroid hormone reduce collagen synthesis and favor net bone loss.
• Low intermittent exposure can stimulate osteoblast activity and increase trabecular bone formation. This anabolic effect is partly mediated by insulin-like growth factors and transforming growth factor beta. Therefore, dose pattern determines whether bone mass rises or falls.

• In primary hyperparathyroidism, commonly caused by parathyroid adenoma, patients may develop hypercalcemia, hypophosphatemia, hypercalciuria, and renal stones.
• Skeletal changes include increased bone resorption and weakened trabecular architecture.
• In hypoparathyroidism, bone turnover is reduced and bone mass may be relatively increased, though bone quality may not always improve.

Actions on GI tract

Acting on intestine, PTH increases absorption of calcium. However, this effect is mostly indirect, mediated through 1,25-dihydroxycholecalciferol, which is formed in kidney by PTH. Thus, the overall effects of PTH are to increase plasma level of calcium and decrease plasma level of phosphate.

Applied Physiology

Hyperparathyroidism

• Hyperparathyroidism refers to excessive secretion of parathyroid hormone. It is classified into primary and secondary forms.

Primary Hyperparathyroidism

• Primary hyperparathyroidism usually results from a parathyroid adenoma, glandular hyperplasia, or rarely carcinoma. It may occur as part of multiple endocrine neoplasia, especially type 1.
• Excess hormone causes hypercalcemia and reduced plasma phosphate.
• Bone resorption increases, producing demineralization, osteopenia, bone pain, and fractures.
• Persistent calcium loss in urine may lead to hypercalciuria and renal stone formation.
• Severe chronic skeletal disease may produce osteitis fibrosa cystica with marrow fibrosis.

Secondary Hyperparathyroidism

• Secondary hyperparathyroidism develops when chronic hypocalcemia persistently stimulates normal parathyroid glands.
• Common causes include chronic kidney disease, vitamin D deficiency, malabsorption, and nutritional rickets or osteomalacia.
• Continuous stimulation causes diffuse glandular hypertrophy or hyperplasia.
• Plasma parathyroid hormone is elevated, but the underlying problem is external to the gland.

Hypoparathyroidism

• Hypoparathyroidism results from deficient secretion or action of parathyroid hormone.
• True gland failure is less common than postoperative or autoimmune causes.
• Major biochemical features are hypocalcemia and elevated plasma phosphate.
• Bone turnover is reduced, so bone density may be increased.

Hypocalcemic Tetany

• Hypocalcemic tetany is an acute state of increased neuromuscular excitability caused by marked reduction in ionized calcium. It commonly occurs after thyroid surgery when parathyroid glands are accidentally removed, damaged, or devascularized.
• Loss of parathyroid hormone rapidly lowers plasma calcium and raises phosphate concentration.
• Symptoms usually appear within 24 to 48 hours after surgery.

Effects of Parathyroidectomy

• Tingling around the mouth, numbness of fingers, and muscle cramps are early symptoms.
• Chvostek sign is contraction of facial muscles after tapping over the facial nerve.
• Trousseau sign is carpal spasm induced by inflating a blood pressure cuff.
• Carpopedal spasm causes painful flexion of wrist, hand, ankle, and foot muscles.
• Generalized muscle twitching or seizures may occur in severe cases.

• Laryngospasm may obstruct the airway and produce dangerous hypoxia.
• Cardiac irritability and prolonged QT interval may also be present.
• Plasma calcium is significantly reduced.
• Plasma phosphate is increased due to lack of renal phosphate excretion. This is a medical emergency requiring prompt treatment.
• Immediate intravenous calcium, commonly calcium gluconate, is given to relieve symptoms.
• Long-term therapy includes oral calcium supplements and active vitamin D preparations.
• Magnesium deficiency should be corrected if present.

Parathyroid Hormone‑related Protein

• Parathyroid hormone-related protein is a peptide that shares structural similarity with parathyroid hormone, especially at the amino-terminal region.
• Because of this similarity, it can activate the PTH1 receptor and produce parathyroid hormone-like effects. It is synthesized in many normal tissues and mainly acts locally through paracrine or autocrine pathways. It has several isoforms generated by alternative messenger ribonucleic acid processing.

Functions of PTHrP

• It promotes proliferation of chondrocytes in developing cartilage and delays premature mineralization of growth plates.
• It acts as a growth factor in tissues such as skin, hair follicles, and mammary gland.
• It is produced in large amounts by the lactating breast and may be present in milk.
• It contributes to placental calcium transport from mother to fetus.
• It is also expressed in kidney and brain, where local regulatory roles are likely.
• Excess secretion of this protein by certain tumors can cause hypercalcemia of malignancy. This commonly occurs in some lung, renal, breast, and squamous cell cancers.

Calcitonin

Source and Structure

• Calcitonin is secreted by parafollicular cells, also called C cells, of the thyroid gland. These cells are derived embryologically from the ultimobranchial body, associated with the pharyngeal pouch system.
• Calcitonin is a peptide hormone composed of 32 amino acids. Its approximate molecular weight is 3,500 daltons.
• Alternative processing of the calcitonin gene in nervous tissue produces calcitonin gene-related peptide.
• Calcitonin gene-related peptide is a potent vasodilator and neuropeptide.

Synthesis, Secretion and Metabolism

Synthesis and Secretion

• The major stimulus for calcitonin release is an increase in plasma calcium concentration.
• Higher calcium levels produce greater hormone secretion.
• Gastrointestinal hormones such as gastrin, cholecystokinin, glucagon, and secretin can stimulate release.
• Gastrin is a particularly strong stimulus.
• Beta-adrenergic agonists, dopamine, and estrogen may also enhance secretion.

Metabolism

• Normal plasma calcitonin concentration is about 10–20 picograms per milliliter.
• Levels may rise markedly in hypercalcemia.
• The hormone is metabolized in the liver and has a short half-life.

Mechanism of Action

• Calcitonin acts through specific membrane receptors on target cells. These receptors are coupled to Gs proteins and activate the adenylate cyclase–cyclic adenosine monophosphate signaling pathway.
• Increased intracellular signaling mediates the biological effects of the hormone.

Physiological Actions

Calcitonin lowers plasma calcium mainly by actions on bone and kidney.

Effects on Bone

• The principal skeletal target is the osteoclast.
• Calcitonin suppresses osteoclastic activity and reduces bone resorption.
• The number and size of active osteoclasts may decrease.
• Reduced bone breakdown limits release of calcium from skeletal stores. Its action on bone calcium turnover is generally opposite to that of parathyroid hormone.
• Calcitonin can lower plasma phosphate concentration. This occurs through reduced bone resorption, increased phosphate deposition in bone, and mild increase in urinary phosphate excretion.

Effects on Kidney

It decreases calcium reabsorption from kidney. Therefore, it produces calciuria. It also causes mild phosphaturia by acting on proximal tubule.

Calcitonin Escape

• Administration of calcitonin initially lowers plasma calcium mainly by inhibiting osteoclastic bone resorption. This hypocalcemic effect gradually diminishes within hours despite continued exposure.
• The phenomenon is called calcitonin escape.
• The exact mechanism is not fully established.
• Likely explanations include receptor desensitization, down-regulation of calcitonin receptors, and compensatory calcium-regulating pathways.
• Because of this short-lived action, calcitonin has limited value for long-term control of chronic hypercalcemia. It may still be useful for temporary reduction of calcium levels in acute settings.

Physiological Significance

• Due to calcitonin escape, persistent excess calcitonin, such as in medullary thyroid carcinoma, usually does not produce major skeletal abnormalities.
• Calcitonin secretion is relatively higher in children and adolescents, suggesting a supportive role in skeletal growth and mineral balance.
• Food intake stimulates gastrointestinal hormones such as gastrin, which can increase calcitonin secretion after meals. This response may help reduce transient postprandial hypercalcemia.
• During pregnancy, maternal calcium is transferred to the fetus for bone development.
• During lactation, calcium is also required for milk production.
• Increased calcitonin may help protect maternal skeleton by opposing excessive osteoclastic resorption.
• Active vitamin D levels also rise during pregnancy to improve calcium absorption.
• Calcitonin and calcitonin gene-related peptide are present in several brain regions. They may function as neuromodulators or co-transmitters.

• Calcitonin gene-related peptide is particularly important in pain pathways and vascular regulation.

Applied Aspects

Clinical Use of Calcitonin

• Calcitonin may be used for short-term treatment of hypercalcemia, especially when rapid reduction of serum calcium is required. It suppresses osteoclastic bone resorption and lowers calcium release from bone. It has also been used in conditions with increased bone turnover, such as Paget disease of bone.
• In some patients, calcitonin may provide analgesic benefit, particularly in acute vertebral fracture pain.

Paget’s Disease

• Paget disease is characterized by excessive bone resorption followed by disorganized compensatory bone formation.
• The resulting bone is enlarged, weak, and structurally abnormal.
• Common manifestations include bone pain, deformity, fractures, and compressive neuropathy.
• Imaging may show mixed lytic and sclerotic areas with cortical thickening.
• Bisphosphonates are the preferred modern treatment because they more effectively inhibit bone resorption.
• Calcitonin is now used less often but remains an alternative when bisphosphonates are unsuitable.

Vitamin D

• Vitamin D increases plasma calcium by enhancing intestinal calcium absorption, renal calcium reabsorption, and controlled mobilization of calcium from bone. It also promotes phosphate absorption and helps maintain mineral balance.

Synthesis of Vitamin D

• Humans obtain vitamin D from skin synthesis and dietary intake.

From Skin

• In the epidermis, ultraviolet B radiation converts 7-dehydrocholesterol into previtamin D3.
• The effective wavelength range is approximately 290–315 nanometers.
• Previtamin D3 then undergoes thermal isomerization to form vitamin D3 over the next few days.
• Moderate sunlight exposure supports production.
• Excessive sunlight does not continuously increase vitamin D because surplus precursors are converted into inactive photoproducts.
• Skin pigmentation, age, sunscreen use, latitude, clothing, and season influence synthesis.

From Diet

• Important food sources include fatty fish, fish liver oils, egg yolk, fortified milk, and liver.
• Dietary requirements vary with age and guidelines; many adults require more than older historical recommendations.
• Vitamin D obtained from food is biologically inactive until metabolized.
• Vitamin D first undergoes hydroxylation in the liver to form 25-hydroxyvitamin D, the major circulating storage form. This reaction is catalyzed by hepatic enzymes.
• A second hydroxylation occurs mainly in the proximal renal tubule by 1-alpha-hydroxylase. This produces 1,25-dihydroxyvitamin D, the active hormonal form.
• Active vitamin D is essential for normal bone mineralization and growth. It supports calcium absorption from the intestine and helps prevent rickets, osteomalacia, and hypocalcemia.
• Parathyroid hormone stimulates renal activation of vitamin D, especially when calcium levels are low.

Mechanism of Action

• Vitamin D receptors are present in intestine, bone, kidney, and many other tissues.
• Active vitamin D binds intracellular nuclear receptors and regulates gene transcription. It increases synthesis of calbindin, a calcium-binding protein that enhances intestinal calcium absorption.

Physiological Actions

• Vitamin D increases plasma calcium and phosphate mainly through actions on the intestine, kidneys, and bone. Its active form is 1,25-dihydroxyvitamin D.
• The intestine is the major target organ for vitamin D. It enhances calcium absorption even when luminal calcium concentration is low.
• Active vitamin D binds intracellular receptors in intestinal epithelial cells and alters gene expression.
• It increases production of calbindin, calcium channels, and transport proteins. These changes improve movement of calcium from the intestinal lumen into blood.
• It also increases absorption of phosphate and magnesium.
• Parathyroid hormone indirectly enhances intestinal calcium absorption by stimulating renal activation of vitamin D.

• Vitamin D works with parathyroid hormone to increase renal calcium reabsorption. It promotes calcium transport proteins in tubular cells.
• Unlike parathyroid hormone, vitamin D tends to increase phosphate reabsorption when overall mineral balance permits. It also helps conserve magnesium.
• Bone cells, especially osteoblasts, contain vitamin D receptors.
• Vitamin D supports osteoblast function and synthesis of bone matrix proteins. It is essential for proper mineralization of newly formed osteoid.
• Deficiency causes poor mineralization, leading to rickets in children and osteomalacia in adults.
• Vitamin D can also promote osteoclast formation indirectly through osteoblast signaling molecules such as receptor activator of nuclear factor kappa-B ligand. This increases bone resorption when calcium demand is high. Therefore, vitamin D has a dual role: it can mobilize calcium acutely, but overall it promotes stronger mineralized bone by improving calcium and phosphate availability.

• Increased intestinal absorption and renal conservation of calcium and phosphate raise plasma mineral availability. This overall effect favors bone mineralization more than bone loss under physiological conditions.
• Vitamin D receptors are present in skeletal muscle, cardiac muscle, immune cells, skin, and endocrine tissues.
• Adequate vitamin D supports muscle strength and normal neuromuscular performance.
• Deficiency may contribute to muscle weakness and falls.
• It influences immune cell differentiation and modulation of inflammatory responses.
• In skin, it supports keratinocyte growth and barrier function.
• It also participates in regulation of cellular growth and gene expression in multiple tissues.

Vitamin D Deficiency

• Vitamin D deficiency causes rickets in children and osteomalacia in adults.
• The primary defect is poor mineralization of osteoid and growing bone.

Causes

• Inadequate dietary intake of vitamin D.
• Limited sunlight exposure.
• Chronic liver disease causing impaired 25-hydroxylation.
• Chronic kidney disease causing reduced 1-alpha-hydroxylation.
• Hypoparathyroidism, which reduces activation of vitamin D.
• Enzyme-inducing anticonvulsants such as phenobarbital.
• Vitamin D receptor defects.
• Hereditary vitamin D-dependent rickets due to enzyme deficiency.

Features

• Calcium and phosphate levels may be reduced or low-normal depending on severity.
• Excess unmineralized osteoid accumulates in cortical and trabecular bone.
• Bone strength decreases, leading to deformity under mechanical stress.

In Children

• Growth plates are affected because bones are still developing.
• Long bones may bend, causing bowing of the legs.
• Delayed growth, widened wrists, frontal bossing, and rachitic chest may occur.

In Adults

• Longitudinal growth is complete, so bowing is less prominent.
• Patients commonly develop diffuse bone pain, proximal muscle weakness, fractures, and vertebral compression.

Treatment

• Early treatment with vitamin D supplementation is essential.
• Adequate calcium intake, sunlight exposure, and correction of the underlying cause are also required.

Vitamin D Excess

• Vitamin D excess usually results from excessive supplementation. It may cause hypercalcemia, hypercalciuria, nephrolithiasis, and hyperphosphatemia.
• Increased bone resorption and soft-tissue calcification can also occur.

Other Hormones Affecting Calcium and Bone Metabolism

Glucocorticoids

Glucocorticoids reduce intestinal calcium absorption and impair bone formation. Chronic excess commonly causes osteoporosis.

Growth Hormone

Growth hormone increases intestinal calcium absorption and stimulates osteoblastic bone formation. Mild urinary calcium loss may also occur.

Growth Factors

Growth factors promote protein synthesis in bone matrix and enhance bone formation.

Insulin

Insulin supports osteoblast activity and skeletal growth. Poorly controlled chronic diabetes may contribute to bone loss.

Thyroid Hormones

Excess thyroid hormones accelerate bone turnover, causing hypercalcemia, hypercalciuria, and long-term bone demineralization.

Estrogen

Estrogen inhibits osteoclastic resorption and helps prevent postmenopausal osteoporosis.

Testosterone

Testosterone maintains normal bone mass and promotes skeletal development.