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Calcitonin

Also known as salmon calcitonin, salcatonin, Miacalcic, Miacalcin, Fortical, Calcimar

Thyroid C-cell hormone; the salmon version is used short-term for hypercalcaemia and Paget disease.

clinically proven Hormonal & sexual approved drug

At a glance

Category
Hormonal & sexual
Status
approved drug
Made from
synthetic The sequence is that of salmon calcitonin, but the product is not made from fish: Miacalcin is chemically synthesised, and Fortical is produced recombinantly in Escherichia coli.
Route
subcutaneous, intramuscular, intravenous infusion; intranasal spray where still marketed
Half-life
roughly 40-60 minutes after subcutaneous or intranasal administration; about 1 hour intravenously
Onset
serum calcium begins to fall within about 2 hours of injection, with the nadir at 6-24 hours; the effect wanes within days because of tachyphylaxis
Molecular weight
3431.9 g/mol (salmon calcitonin)
Sequence
Salmon calcitonin: CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP-NH2 (32 amino acids, disulfide bridge between Cys1 and Cys7, C-terminal proline amide). Human calcitonin is CGNLSTCMLGTYTQDFNKFHTFPQTAIGVGAP-NH2 and differs at 16 of 32 positions.

Salmon calcitonin injection remains authorised in the EU and US, but for restricted, short-term indications only. Following a CHMP review under Article 31, the EMA recommended in July 2012 that calcitonin be used only short-term and that the nasal spray be withdrawn from the EU market, because long-term use was associated with an increased rate of malignancy 23. Nasal calcitonin remains marketed in the US.

Doping status: Not listed by WADA

Checked against the WADA 2026 Prohibited List. For a specific product and country, Global DRO is the lookup athletes are expected to use — the List names substances, not brand names.

Being a non-human sequence is nonetheless why the immune system reacts to it: the label reports circulating antibodies to calcitonin salmon in about half of the patients with Paget's disease tested after 2 to 18 months, and says high titres usually mean loss of response - so a patient who responded at first and then stopped responding should be considered for antibody formation rather than dose escalation 4. That is an efficacy problem, not an allergy. The label carries no caution about fish allergy at all; its only hypersensitivity guidance is to consider skin testing in patients suspected of hypersensitivity to calcitonin salmon itself 4.

Mechanism of action

Calcitonin is secreted by the parafollicular C cells of the thyroid in response to rising serum calcium and acts as a physiological counterweight to parathyroid hormone. It binds the calcitonin receptor, a class B G-protein-coupled receptor expressed at very high density on osteoclasts, signalling mainly through Gs and cAMP. The immediate effect on the osteoclast is dramatic and directly observable: the cell retracts, loses its ruffled border and sealing zone, and stops resorbing bone. This so-called Q effect (quiescence) occurs within minutes.

Salmon calcitonin is used clinically rather than the human form because it binds the human calcitonin receptor with substantially higher affinity and has a longer plasma residence, giving roughly 20-50 times the potency of human calcitonin on a molar basis. The cost of this is immunogenicity: neutralising antibodies to the fish sequence develop in a proportion of long-term users.

Calcitonin also acts on the kidney, increasing urinary excretion of calcium, phosphate, sodium and magnesium by reducing tubular reabsorption. In acute hypercalcaemia the combination of blocked bone resorption and increased renal calcium loss is what produces the rapid onset — faster than bisphosphonates, which is the entire clinical rationale for using it.

The benefit does not last. Calcitonin receptors on osteoclasts are downregulated within 24-72 hours of continuous exposure, so the calcium-lowering effect escapes after two to three days. Calcitonin is therefore a bridge to a bisphosphonate or denosumab, not a treatment in its own right. A separate analgesic effect in acute vertebral fracture pain is well described but poorly explained; central mechanisms involving beta-endorphin release and serotonergic pathways have been proposed without being established.

What the research shows

Calcitonin's acute calcium-lowering and analgesic effects are well documented, but its long-term osteoporosis evidence was always weak and has now been outweighed by a malignancy signal. The trajectory of this drug is a useful illustration of a compound whose indications narrowed as better evidence and better alternatives arrived.

Research in humans

The PROOF trial (Chesnut et al., American Journal of Medicine, 2000; n=1255 postmenopausal women, 5 years) found that nasal salmon calcitonin 200 IU daily reduced new vertebral fractures by 33% versus placebo (RR 0.67) 1. The result has been widely criticised: the 100 IU and 400 IU arms showed no significant benefit, so there was no dose-response relationship, and roughly 60% of participants dropped out before the end 1. In acute hypercalcaemia of malignancy, calcitonin lowers serum calcium by approximately 0.5-1.0 mmol/l within hours, with escape by 48-72 hours. Meta-analysis of randomised trials submitted to the EMA showed higher malignancy rates in calcitonin-treated participants than in controls 2, the excess ranging from about 0.7% in oral calcitonin trials to about 2.4% in nasal spray trials.

Animal and lab research

Early animal work in rats and rabbits established the osteoclast quiescence effect and receptor pharmacology. The relevance of the animal data to the malignancy question is limited; the safety signal came from pooled human randomised trials, not from carcinogenicity studies.

Caveats. PROOF is the weakest fracture-endpoint dataset among osteoporosis drugs: no dose-response, very high attrition, and manufacturer sponsorship. The malignancy signal is itself imperfect — it comes from meta-analysis of trials not designed to detect cancer, the mechanism is unknown, and the absolute excess is small. Regulators nonetheless judged that for osteoporosis, where safer and more effective alternatives exist, even a modest and uncertain cancer risk was not acceptable 2. For the remaining short-term indications the benefit-risk balance was considered to remain favourable 2.

What it is used for

  • Hypercalcaemia, as a rapid short-term bridge until a bisphosphonate or denosumab takes effect 4
  • Symptomatic Paget disease of bone in patients who do not respond to, or cannot take, alternative treatments 4 (in the EU limited to a maximum of 3 months, exceptionally 6)
  • Prevention of acute bone loss from sudden immobilisation, such as after recent osteoporotic fracture — in the EU limited to 2 weeks, maximum 4 weeks
  • Analgesia in acute vertebral fracture pain (used in some settings, evidence modest)
  • Complex regional pain syndrome (off-label, limited and inconsistent evidence)
  • No longer an accepted treatment for osteoporosis in the EU; the nasal spray was withdrawn for that indication in 2012-2013

Dosing

Dose
Every figure is in international units, and they are set out per indication in the notes below. The hypercalcaemia dose is the only weight-based one; the others are absolute. Note that IU measure biological activity, not mass — 100 IU of salmon calcitonin is roughly 17 mcg, and no calcitonin dose should ever be entered into a milligram field.
Frequency
Twice to four times daily for hypercalcaemia; once daily or on alternate days for the other indications
Route
Subcutaneous or intramuscular; slow intravenous infusion in 500 ml of 0.9% sodium chloride over at least 6 hours for severe hypercalcaemia
Duration
Deliberately short. EU labels cap immobilisation use at 2-4 weeks and Paget disease at around 3 months. Hypercalcaemia treatment rarely exceeds a few days because the effect escapes.
  • Hypercalcaemia, subcutaneous or intramuscular: 4 IU per kilogram of body weight every 12 hours, increased if needed to 8 IU/kg every 12 hours and, exceptionally, 8 IU/kg every 6 hours 4. This is the only weight-based calcitonin regimen — for a 70 kg adult the starting dose is about 280 IU, which is well above every absolute figure quoted for the other indications.
  • Paget disease of bone, subcutaneous or intramuscular: 100 IU daily 4, or every other day. An absolute dose, not per kilogram.
  • Acute immobilisation bone loss, subcutaneous or intramuscular: 100 IU daily, or 50 IU twice daily. An absolute dose.
  • Nasal spray, US market only: 200 IU as one spray daily, alternating nostrils. The nasal figure belongs to the nasal device and does not transfer to injection.
  • Tachyphylaxis is the norm rather than the exception in hypercalcaemia: expect the calcium-lowering effect to fade after 48-72 hours. Definitive treatment with a bisphosphonate or denosumab should start at the same time.
  • Adequate calcium and vitamin D intake is advised during treatment for Paget disease or immobilisation, to avoid provoking secondary hyperparathyroidism.
  • The doses above are the licensed EU and US regimens from official product information. This is reference material, not treatment advice.
  • Long-term daily use for osteoporosis, which was standard practice for years, is no longer supportable and is not licensed in the EU.

These figures describe what the literature and published protocols report. They are not advice and not a dosing instruction.

Protocols

Miacalcin injection (hypercalcaemia)

approved product information

Source: MIACALCIN (calcitonin salmon) injection prescribing information, DailyMed

Starting dose4 units/kg every 12 hours, subcutaneously or intramuscularly
After 1 to 2 days, if the response is unsatisfactory8 units/kg every 12 hours
After a further two days, if still unsatisfactory8 units/kg every 6 hours - the maximum

An adjunct for the first day or two of a hypercalcaemic emergency, alongside hydration and other agents, not a treatment on its own. Tachyphylaxis develops within days, which is why the schedule escalates rather than continues.

Miacalcin injection (Paget disease of bone)

approved product information

Source: MIACALCIN (calcitonin salmon) injection prescribing information, DailyMed

Daily100 units per day, subcutaneously or intramuscularly

Adequate calcium and vitamin D intake is assumed throughout. This is the US schedule; after the 2012 European review of a small excess of malignancy with long-term use, EU authorities restricted Paget treatment to patients unresponsive to alternatives and limited courses to three months, so the two product informations do not agree on duration.

Miacalcin injection (postmenopausal osteoporosis)

approved product information

Source: MIACALCIN (calcitonin salmon) injection prescribing information, DailyMed

Daily, in women more than 5 years postmenopausal100 units per day subcutaneously or intramuscularly, with at least 1,000 mg elemental calcium and 400 IU vitamin D daily

This indication no longer exists in the EU: the 2012 review withdrew calcitonin for osteoporosis entirely, including the nasal spray, on the grounds that the small fracture benefit did not outweigh the malignancy signal. It survives on the US label, which is the only reason this schedule can still be quoted.

Schedules are reproduced as their source states them. Units, IU and milligrams explains why the figures are not interchangeable between products.

Reconstitution

Vial sizes
1 ml ampoule containing 50 IU, 1 ml ampoule containing 100 IU, nasal spray delivering 200 IU per actuation (US)
Solvent
0.9% sodium chloride, only when diluting for intravenous infusion
Storage
Ampoules refrigerated at 2-8 °C, protected from light, not frozen. Nasal spray refrigerated until first use, then kept at room temperature and used within the period specified on the label (typically 30-35 days).

Worked example

Not a reconstitution product. Marketed salmon calcitonin injection is a ready-to-use sterile aqueous solution in ampoules; nothing is dissolved from powder. For intravenous use in severe hypercalcaemia the required dose is diluted into 500 ml of 0.9% sodium chloride and infused over at least 6 hours.

Calcitonin adsorbs to plastic surfaces, which is why the label specifies preparing intravenous infusions immediately before use rather than storing them. Note also that dosing is expressed in international units, not milligrams — 100 IU of salmon calcitonin is roughly 17 mcg.

Safety

Side effects

  • Nausea with or without vomiting, about 10%, especially with the first doses and often reduced by giving the injection in the evening 4
  • Flushing of the face or hands, about 2-5%, with a sensation of warmth, typically within 10-20 minutes of injection 4
  • Injection site inflammation, about 10%, with pain and induration 4
  • Nasal irritation, dryness, crusting, rhinitis and epistaxis with the nasal spray
  • Hypocalcaemia, usually transient and asymptomatic, occasionally with paraesthesia, tetany or seizures 4
  • Taste disturbance, dizziness and headache
  • Polyuria and increased urinary frequency
  • Development of neutralising antibodies with prolonged use, which can cause loss of response to treatment 4
  • Hypersensitivity reactions including reports of fatal anaphylaxis; a skin test may be considered in patients with suspected sensitivity 4
  • Increased incidence of malignancy with long-term use. Pooled randomised trial data showed an absolute excess of roughly 0.7% (oral formulations) to 2.4% (nasal spray) over comparator groups 2; the US label reports an overall malignancy rate of 4.1% with calcitonin salmon against 2.9% with placebo 4. The mechanism is unknown and causality is not established, but this finding is the reason the nasal spray was withdrawn in the EU and long-term use is no longer permitted 23

Do not use if

  • Hypersensitivity to calcitonin salmon or any of the excipients 4
  • Hypocalcaemia
  • Long-term treatment of osteoporosis — not merely discouraged but no longer an authorised indication in the EU 23
  • Pregnancy and breastfeeding: not recommended, as calcitonin has been shown to cross into milk and to reduce fetal weight in animals
  • Caution in patients with a history of allergy to fish or peptide drugs
  • Caution in patients with a personal history of malignancy, given the trial-level cancer signal, particularly if any extended use is contemplated

Interactions

Calcitonin may reduce plasma lithium concentrations through increased urinary clearance; lithium levels should be monitored and the dose may need adjusting 4. Concurrent bisphosphonates or denosumab add to the hypocalcaemic effect, which is clinically intended in hypercalcaemia but requires monitoring. Calcitonin reduces the renal clearance and volume of distribution of some agents; the interaction is not systematically characterised for most drugs. Calcium and vitamin D supplements counteract the hypocalcaemic effect and are usually given deliberately during treatment of Paget disease and immobilisation bone loss.

Sources