Pharmacology of Calcitonin

Introduction/Overview

Calcitonin is a polypeptide hormone primarily involved in calcium and bone homeostasis. It is secreted by the parafollicular cells (C-cells) of the thyroid gland in mammals, though in non-mammalian vertebrates such as fish, reptiles, and birds, it is produced in the ultimobranchial glands. The pharmacological interest in calcitonin stems from its potent hypocalcemic and hypophosphatemic effects, which have been harnessed for therapeutic purposes in various metabolic bone disorders. The discovery of calcitonin in the early 1960s, following the identification of parathyroid hormone, completed the classic endocrine triad regulating plasma calcium levels, alongside parathyroid hormone and vitamin D.

The clinical relevance of calcitonin has evolved significantly. Historically, it represented a first-line therapeutic option for postmenopausal osteoporosis and Paget’s disease of bone. While its use in chronic osteoporosis management has diminished with the advent of more potent antiresorptive agents like bisphosphonates and denosumab, calcitonin retains important niches in clinical practice. Its rapid onset of action makes it valuable in the acute management of hypercalcemia and for the relief of pain associated with osteoporotic vertebral fractures. Furthermore, the measurement of serum calcitonin serves as a critical tumor marker for medullary thyroid carcinoma, a malignancy arising from the C-cells.

The primary learning objectives for this chapter are:

• To describe the physiological role of endogenous calcitonin and the pharmacological properties of its therapeutic analogues.
• To explain the molecular mechanism of action of calcitonin, including receptor binding and intracellular signaling pathways.
• To analyze the pharmacokinetic profiles of different calcitonin formulations (salmon, human, eel) and their clinical implications.
• To evaluate the approved therapeutic indications, common adverse effects, and significant drug interactions associated with calcitonin therapy.
• To apply knowledge of calcitonin pharmacology to special patient populations, including those with renal impairment or in palliative care settings.

Classification

Calcitonin is classified as a polypeptide hormone and a hypocalcemic agent. From a therapeutic perspective, it belongs to the broader category of antiresorptive agents used in bone metabolism disorders, though its mechanism and potency differ from other drugs in this class.

Chemical and Source-Based Classification

Therapeutically available calcitonins are categorized based on their source, which dictates their amino acid sequence, receptor affinity, and potency.

• Salmon Calcitonin: This is the most widely used therapeutic form. It is a 32-amino acid linear polypeptide. Salmon calcitonin exhibits greater receptor-binding affinity and metabolic stability in humans compared to human calcitonin, resulting in a longer duration of action and higher potency (approximately 40-50 times more potent on a molar basis). Its resistance to metabolic degradation is a key pharmacological advantage.
• Human Calcitonin: Identical in sequence to endogenous human hormone. It is less potent and has a shorter half-life than the salmon analogue, which has limited its therapeutic use.
• Eel Calcitonin (Elcatonin): Used primarily in Japan and some Asian countries. Its pharmacological profile is similar to, though distinct from, salmon calcitonin.

All therapeutic calcitonins share a common structural motif: a disulfide bridge between cysteine residues at positions 1 and 7, forming a seven-membered ring at the N-terminus, which is essential for receptor activation. The C-terminal prolineamide is also crucial for biological activity.

Formulation Classification

Calcitonin is available in several dosage forms, which significantly influence its pharmacokinetics and clinical application:

• Parenteral Formulations: These include subcutaneous and intramuscular injections. They provide rapid and reliable systemic absorption, making them suitable for acute conditions like hypercalcemic crisis.
• Intranasal Spray: This formulation was developed to improve patient compliance for chronic conditions like osteoporosis. Absorption occurs through the nasal mucosa, bypassing gastrointestinal degradation. Bioavailability is low (approximately 3% of a parenteral dose) but sufficient for a clinical effect on bone, with a reduced incidence of systemic side effects.
• Oral and Rectal Formulations: These are available in some regions but are not widely used due to very low bioavailability resulting from extensive proteolytic degradation in the gastrointestinal tract.

Mechanism of Action

The primary pharmacological actions of calcitonin are mediated through its binding to specific high-affinity receptors on target cells, predominantly osteoclasts and renal tubular cells.

Receptor Interactions

The calcitonin receptor (CTR) is a member of the class B G-protein-coupled receptor (GPCR) family. It is encoded by the CALCR gene. Receptor activation occurs upon binding of the hormone’s N-terminal ring structure. The CTR can couple to multiple G-proteins, primarily G_s and G_q, leading to the activation of several intracellular signaling cascades. The receptor’s activity and specificity can be further modulated by interaction with receptor activity-modifying proteins (RAMPs). The combination of CTR with RAMP1 forms the calcitonin gene-related peptide (CGRP) receptor, illustrating the complexity of this receptor family. However, the classic hypocalcemic action of calcitonin is mediated through the CTR independent of RAMPs.

Cellular and Molecular Mechanisms

The hypocalcemic effect of calcitonin is achieved through two principal mechanisms: inhibition of bone resorption and enhancement of renal calcium excretion.

Action on Bone (Osteoclast Inhibition): Calcitonin exerts its most potent effect by directly inhibiting the activity and formation of osteoclasts. Upon binding to CTRs on the osteoclast surface, several intracellular events are triggered:

• Activation of adenylate cyclase via G_s coupling, leading to a rapid increase in intracellular cyclic adenosine monophosphate (cAMP).
• Activation of phospholipase C via G_q coupling, resulting in increased inositol trisphosphate (IP₃) and diacylglycerol (DAG), which mobilizes intracellular calcium stores and activates protein kinase C (PKC).
• The rise in cAMP and activation of PKC pathways lead to cytoskeletal rearrangement, causing the osteoclast to retract from the bone surface (quiescence).
• There is a subsequent inhibition of the secretion of proteolytic enzymes (e.g., cathepsin K) and protons (via the vacuolar H⁺-ATPase) into the resorption lacuna.
• Long-term administration may also suppress osteoclast progenitor differentiation and promote osteoclast apoptosis.

This rapid inhibition of osteoclastic bone resorption reduces the efflux of calcium and phosphate from bone into the extracellular fluid.

Action on the Kidney: Calcitonin increases the renal excretion of calcium, phosphate, sodium, magnesium, and chloride. It acts on CTRs in the thick ascending limb of the loop of Henle and the distal convoluted tubule.

• The primary mechanism involves inhibition of tubular reabsorption of these ions. The exact transporters affected are not fully delineated but may involve modulation of the Na⁺/K⁺/2Cl^– cotransporter and calcium channels like TRPV5.
• The phosphaturic effect is independent of parathyroid hormone and contributes to the overall reduction in serum phosphate.

Other Actions: Calcitonin receptors are found in other tissues, including the central nervous system, gastrointestinal tract, and immune cells, which may account for additional effects:

• Analgesic Effect: An important clinical property, particularly beneficial in bone pain from fractures or Paget’s disease. The mechanism is likely central, involving binding to receptors in periaqueductal gray matter and modulation of β-endorphin release. It may also have a peripheral anti-inflammatory component.
• Gastrointestinal Effects: Can reduce gastric acid and pepsin secretion, and slow intestinal motility, though these are minor clinical effects.

Pharmacokinetics

The pharmacokinetic profile of calcitonin varies considerably depending on the source (salmon vs. human) and the route of administration.

Absorption

Parenteral Administration (Subcutaneous/Intramuscular): Absorption from injection sites is rapid and complete. Following a subcutaneous or intramuscular injection, peak plasma concentrations (C_max) are typically achieved within 15 to 30 minutes. Bioavailability by these routes approaches 100%.

Intranasal Administration: Absorption through the nasal mucosa is passive and variable. Bioavailability is low, averaging approximately 3% (range 0.3% to 30%) of a comparable subcutaneous dose. Factors such as rhinitis, nasal anatomy, and administration technique can significantly influence absorption. C_max is reached within 30 to 40 minutes.

Oral Administration: Orally administered calcitonin is extensively degraded by proteolytic enzymes in the stomach and intestine, rendering it virtually inactive systemically. Any oral bioavailability is negligible for therapeutic purposes.

Distribution

Calcitonin distributes rapidly into the extracellular fluid. Its volume of distribution is relatively small, approximately 0.15 to 0.3 L/kg, indicating limited tissue penetration beyond the plasma and interstitial fluid. It does not cross the blood-brain barrier to a significant degree under normal conditions, though some central effects imply limited access or action at circumventricular organs. Plasma protein binding is not extensive.

Metabolism

Calcitonin is metabolized primarily via proteolytic degradation in the kidneys, blood, and peripheral tissues. The kidneys play a predominant role in its catabolism. The enzyme neutral endopeptidase (NEP) is a key mediator of its breakdown. Salmon calcitonin is more resistant to metabolic degradation than the human hormone due to amino acid substitutions, contributing to its longer half-life and greater in vivo potency. Hepatic metabolism appears to be minimal.

Excretion

The metabolites of calcitonin are excreted primarily by the kidneys. Less than 2% of an administered dose is recovered as intact hormone in urine. The elimination half-life (t_1/2) differs markedly between preparations:

• Salmon Calcitonin (intravenous): t_1/2 α (distribution) is about 10 minutes; t_1/2 β (elimination) ranges from 50 to 80 minutes.
• Human Calcitonin (intravenous): Has a much shorter elimination half-life of approximately 10 to 15 minutes.
• Intranasal Salmon Calcitonin: The apparent half-life is longer due to the absorption rate-limiting process, but the systemic elimination phase mirrors that of parenteral administration.

The total body clearance of calcitonin is high, often exceeding renal plasma flow, indicating significant extrarenal metabolism.

Therapeutic Uses/Clinical Applications

The therapeutic applications of calcitonin are based on its antiresorptive, hypocalcemic, and analgesic properties.

Approved Indications

Postmenopausal Osteoporosis: Calcitonin is approved for the treatment of postmenopausal osteoporosis in women who are at least five years post-menopause. It is considered a second or third-line agent after bisphosphonates, denosumab, or teriparatide, due to its relatively modest effect on bone mineral density (BMD) and fracture risk reduction. Its use is often reserved for patients who cannot tolerate other therapies, largely due to its favorable side effect profile (excluding nasal administration) and analgesic benefit. The intranasal formulation is most common for this chronic use.

Paget’s Disease of Bone (Osteitis Deformans): Calcitonin is effective in suppressing the excessive bone turnover characteristic of Paget’s disease. It can reduce bone pain, decrease elevated serum alkaline phosphatase and urinary hydroxyproline levels, and promote healing of osteolytic lesions. While bisphosphonates are now first-line due to their potency and duration of action, calcitonin remains an option, particularly for patients requiring rapid symptom relief or who have contraindications to bisphosphonates.

Hypercalcemia: Particularly useful in the management of hypercalcemia of malignancy. Its hypocalcemic effect begins within hours, making it a valuable agent for initial management alongside intravenous rehydration and bisphosphonates. The effect on serum calcium is often transient (tachyphylaxis may develop), so it is typically used as a bridge until the slower-onset but more sustained effect of intravenous bisphosphonates takes hold.

Acute Bone Pain: Due to its analgesic properties, calcitonin is indicated for the relief of pain associated with acute osteoporotic vertebral compression fractures. The parenteral route is typically used for this indication.

Off-Label and Investigational Uses

Complex Regional Pain Syndrome (CRPS): Some evidence supports the use of intranasal or subcutaneous calcitonin for pain relief in CRPS, though data are not conclusive.

Prevention of Postmenopausal Bone Loss: Used in early postmenopausal women to prevent rapid bone loss, though other agents are generally preferred.

Osteogenesis Imperfecta: Has been used historically in children to reduce fracture frequency, but evidence is limited.

Diabetic Charcot Neuroarthropathy: Occasionally used for its putative antiresorptive and analgesic effects.

Adverse Effects

The adverse effect profile of calcitonin is route-dependent. Generally, side effects are more frequent and pronounced with parenteral administration.

Common Side Effects

Gastrointestinal Effects: Nausea, vomiting, anorexia, and abdominal pain are among the most frequent side effects, occurring in up to 10% of patients receiving parenteral therapy. These effects often diminish with continued use.

Flushing: A sensation of warmth or flushing of the face, ears, and hands is common shortly after injection.

Local Reactions: Inflammation, pain, or swelling at the site of injection. For intranasal spray, local nasal side effects are predominant and include rhinitis, nasal dryness, epistaxis, irritation, and ulceration of the nasal mucosa.

Hypersensitivity Reactions: Skin rashes, pruritus, and rarely, more systemic allergic manifestations can occur. A skin test is recommended prior to initiating therapy, particularly with salmon calcitonin, due to its foreign protein nature.

Serious/Rare Adverse Reactions

Anaphylaxis and Severe Allergic Reactions: Although rare, anaphylactic shock has been reported, necessitating the availability of emergency equipment during initial administration.

Hypocalcemia: Symptomatic hypocalcemia (tetany, paresthesias) is uncommon but can occur, especially with overzealous dosing in the treatment of hypercalcemia or in patients with pre-existing hypoparathyroidism.

Increased Risk of Malignancy: Long-term epidemiological data from clinical trials and post-marketing surveillance have suggested a small but statistically significant increased risk of various cancers (e.g., prostate, liver, pancreas) associated with long-term use of intranasal salmon calcitonin. This has led regulatory agencies like the European Medicines Agency to restrict its long-term use in chronic conditions like osteoporosis, limiting treatment duration. The mechanism for this potential risk is not understood.

Antibody Formation: Non-neutralizing antibodies develop in a significant proportion of patients (30-70%) receiving salmon calcitonin, which typically do not affect efficacy. The development of neutralizing antibodies is less common (≈5%) but can lead to clinical resistance or “escape” phenomenon, particularly in Paget’s disease.

Drug Interactions

Formal pharmacokinetic drug interaction studies with calcitonin are limited. Most interactions are pharmacodynamic in nature.

Major Drug-Drug Interactions

Lithium: Concomitant use may lead to a reduction in plasma lithium concentrations, potentially necessitating a dose adjustment. The mechanism may involve calcitonin-induced increases in renal lithium excretion.

Other Hypocalcemic Agents: Concurrent use with potent hypocalcemic drugs like bisphosphonates, denosumab, or phosphate supplements may have additive effects, increasing the risk of symptomatic hypocalcemia. Serum calcium monitoring is advised.

Loop Diuretics (e.g., Furosemide): Loop diuretics inhibit calcium reabsorption in the thick ascending limb and can enhance the calcitonin-induced calciuresis, potentially exacerbating hypocalcemia.

Contraindications

Hypersensitivity: Contraindicated in patients with a known hypersensitivity to calcitonin (salmon or human) or any component of the formulation.

Pre-existing Severe Hypocalcemia: Calcitonin is contraindicated in patients with clinically significant hypocalcemia.

Special Considerations

Use in Pregnancy and Lactation

Pregnancy (Category C): Animal reproduction studies have shown adverse effects (fetal resorption). There are no adequate and well-controlled studies in pregnant women. Calcitonin does not cross the human placenta in significant amounts, but its use during pregnancy is not recommended unless the potential benefit justifies the potential risk to the fetus. It is not indicated for the treatment of pregnancy-associated or lactation-associated osteoporosis.

Lactation: It is not known whether calcitonin is excreted in human milk. Given that it is a peptide, systemic absorption by the nursing infant is unlikely. However, caution is generally advised, and use during breastfeeding is not recommended.

Pediatric and Geriatric Considerations

Pediatric Use: Safety and effectiveness in children have not been established for most indications, except in specific contexts like juvenile Paget’s disease or osteogenesis imperfecta under specialist supervision. Dosing must be carefully individualized.

Geriatric Use: No specific dose adjustment is routinely required based on age alone. However, the elderly may have age-related renal impairment, which could theoretically affect calcitonin clearance, though this is not clinically significant for dosing. The increased prevalence of osteoporosis and fracture risk in this population makes careful consideration of the risk-benefit profile, particularly regarding long-term cancer risk, essential.

Renal and Hepatic Impairment

Renal Impairment: Since the kidney is a major site of calcitonin metabolism, patients with severe renal impairment (e.g., end-stage renal disease) may have reduced clearance, potentially leading to higher and more prolonged systemic exposure. While specific dosing guidelines are not well-established, caution and possibly dose reduction should be considered in severe renal failure. Monitoring for signs of hypocalcemia is prudent.

Hepatic Impairment: The liver plays a minimal role in calcitonin metabolism. Therefore, dose adjustment is not typically necessary in patients with hepatic impairment.

Summary/Key Points

• Calcitonin is a polypeptide hormone that lowers serum calcium and phosphate primarily by inhibiting osteoclast-mediated bone resorption and increasing renal excretion of these ions.
• Salmon calcitonin is the predominant therapeutic form due to its higher potency and longer half-life compared to human calcitonin, resulting from greater receptor affinity and metabolic stability.
• The mechanism of action involves binding to a class B GPCR on osteoclasts, activating cAMP and PKC pathways, leading to osteoclast quiescence and inhibition of bone resorption. It also has central analgesic properties.
• Pharmacokinetics are route-dependent: parenteral administration offers complete bioavailability and rapid onset; intranasal administration provides low (~3%) but therapeutically sufficient bioavailability for chronic bone conditions, with fewer systemic side effects.
• Key clinical indications include second-line treatment for postmenopausal osteoporosis (with restrictions on long-term use due to cancer risk), Paget’s disease of bone, adjunctive management of hypercalcemia of malignancy, and relief of acute bone pain from vertebral fractures.
• Common adverse effects are gastrointestinal disturbances (nausea) and flushing with injections, and local nasal symptoms with the intranasal spray. Serious risks include hypersensitivity reactions and a potential small increased risk of malignancy with long-term intranasal use.
• Significant drug interactions are primarily pharmacodynamic, such as additive hypocalcemia with bisphosphonates or enhanced lithium excretion.
• Use in pregnancy and lactation is not recommended. Dose adjustment may be considered in severe renal impairment, but is not necessary for hepatic impairment or advanced age alone.

Clinical Pearls:

1. The rapid hypocalcemic effect of parenteral calcitonin makes it a useful acute intervention for severe hypercalcemia, but tachyphylaxis often develops within days, necessitating transition to a bisphosphonate for sustained control.
2. For chronic osteoporosis management, the modest BMD benefits of calcitonin must be weighed against the potential cancer risk associated with long-term intranasal use, limiting its role primarily to patients intolerant of first-line agents who also derive analgesic benefit.
3. The development of non-neutralizing antibodies is common with salmon calcitonin and usually irrelevant; however, the emergence of neutralizing antibodies should be suspected if a patient with Paget’s disease experiences a loss of biochemical response (“escape phenomenon”).
4. Administering the subcutaneous injection at bedtime can help mitigate bothersome flushing and gastrointestinal side effects, as the patient may sleep through them.
5. Proper technique for intranasal administration (alternating nostrils, priming the spray, avoiding sneezing or blowing the nose immediately after) is crucial to ensure consistent drug delivery and minimize local irritation.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
5. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.