Salmon calcitonin
salcatonin, calcitonin salmon, synthetic salmon calcitonin, sCT
Salmon calcitonin is a 32-amino-acid hormone from the ultimobranchial gland of salmon that lowers blood calcium by switching off osteoclasts. It is far more potent at the human calcitonin receptor than human calcitonin itself, which is why the fish version became the medicine. Once widely prescribed for osteoporosis, its use was heavily restricted in Europe in 2012 after pooled trial data showed a small excess of cancers with long-term treatment.
Mechanism
Salmon calcitonin acts at the calcitonin receptor, a class B G-protein-coupled receptor densely expressed on the osteoclast plasma membrane and also present in kidney and central nervous system. Receptor occupancy raises intracellular cyclic AMP and calcium and produces two rapid and morphologically striking effects on the osteoclast: loss of the ruffled border and the actin sealing zone that the cell needs to acidify the resorption lacuna (the Q effect, for quiescence), and retraction and immobilisation of the cell (the R effect). Bone resorption therefore stops within minutes, before any change in osteoclast number. Because the effect is on osteoclast function rather than survival, it is reversible and prone to tachyphylaxis.
At the kidney, calcitonin receptor activation reduces tubular reabsorption of calcium and phosphate, increasing their urinary excretion and contributing to the acute calcium-lowering effect. Central actions on calcitonin receptors in the hypothalamus and elsewhere are the presumed basis of the analgesic effect claimed for the hormone, possibly involving beta-endorphin release and serotonergic modulation, although this mechanism is much less firmly established than the skeletal one. Salmon calcitonin is roughly 40 to 50 times more potent than human calcitonin in humans, a combination of higher receptor affinity, slower dissociation and a longer plasma half-life arising from sequence differences in the mid-region. The same foreignness that gives potency also drives neutralising antibody formation, which along with receptor downregulation explains the well-described escape phenomenon in which the calcium-lowering effect wanes over weeks of continuous use.
What the research shows
The largest fracture trial, PROOF, randomised 1,255 postmenopausal women with osteoporosis to nasal salmon calcitonin at 100, 200 or 400 IU daily or placebo for five years. Only the 200 IU dose reduced new vertebral fractures significantly, by about 33 per cent; neither the lower nor the higher dose separated from placebo, and no effect on non-vertebral or hip fracture was demonstrated. Roughly 60 per cent of participants withdrew before the end. The absent dose-response and the attrition have led many methodologists to treat PROOF as hypothesis-generating rather than confirmatory, and it remains the weakest headline fracture result among the osteoporosis drug classes. Bone mineral density gains with calcitonin are consistently small, typically 1 to 2 per cent at the spine.
The analgesic claim has a similarly uneven evidence base. A systematic review and meta-analysis of calcitonin for the pain of osteoporotic vertebral compression fracture found a benefit in recent fractures but not in remote ones, on the basis of small, mostly older, often poorly blinded trials. Enthusiasm for an oral formulation was largely extinguished by negative phase 3 programmes: oral salmon calcitonin failed to meet its co-primary structural and symptomatic endpoints across two phase 3 trials in knee osteoarthritis, and the osteoporosis oral programme did not deliver a convincing fracture benefit. The decisive development was the European review under Article 31 of Directive 2001/83/EC, procedure EMEA/H/A-31/1291. Pooling randomised and observational data across formulations, the CHMP found a higher proportion of cancers of various types in long-term calcitonin recipients than in controls, with the absolute excess ranging from about 0.7 per cent for oral formulations to 2.4 per cent for the nasal spray. The Committee adopted its opinion on 19 July 2012 and the European Commission decision followed on 13 February 2013: the benefit no longer outweighed the risk in osteoporosis at all, the nasal formulation was withdrawn entirely, and the injectable was restricted to short courses in Paget's disease of bone, hypercalcaemia of malignancy and acute bone loss from sudden immobilisation. A US advisory committee reached a similar view on the nasal spray in 2013, though the FDA did not withdraw the approval and instead updated the labelling with malignancy information.
Evidence assessment
Mixed evidence
Human randomised trials exist in reasonable number, including a five-year fracture trial and long-standing approved labelling for hypercalcaemia and Paget's disease. But the pivotal fracture evidence showed no dose-response and suffered heavy attrition, the analgesic evidence rests on small older trials, oral development failed across two phase 3 trials, and a regulator-level review concluded the benefit-risk balance was unfavourable in the largest indication. Calling this strong would misrepresent it.
Tiers are applied consistently across the library and re-checked when new trials read out. Read the grading method.
Key studies
A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures study Preclinical only
Only the 200 IU dose significantly reduced new vertebral fractures (about 33 per cent relative reduction). Neither 100 IU nor 400 IU differed from placebo, so no dose-response was demonstrated. No effect on non-vertebral or hip fracture. Approximately 60 per cent of participants withdrew before study end, substantially weakening the result.
Article 31 referral: calcitonin-containing medicines, CHMP outcome Preclinical only
A higher proportion of long-term calcitonin recipients developed cancers of various types than controls, with an absolute excess of roughly 0.7 per cent for oral and 2.4 per cent for nasal formulations. Nasal spray formulations were withdrawn and injectable use was restricted to short courses for Paget's disease (normally up to three months), hypercalcaemia of malignancy and immobilisation-related bone loss (maximum four weeks). Use in osteoporosis was stopped.
Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials Preclinical only
A clear negative result. Oral salmon calcitonin did not meet its co-primary structural and symptomatic endpoints, and the development programme for this indication was not pursued. This is an important counterweight to enthusiasm for calcitonin as a cartilage-protective or analgesic agent.
Safety
The most frequent adverse effects of the injectable form are nausea, vomiting, flushing of the face and hands, and injection-site inflammation; nasal formulations caused rhinitis, nasal congestion, discharge, sneezing, epistaxis and, less often, nasal ulceration. Hypersensitivity reactions including anaphylaxis have been reported, and because the peptide is of fish origin, skin testing before first exposure has historically been advised in some settings. Neutralising antibodies form in a substantial minority with prolonged use and contribute, along with receptor downregulation, to loss of effect over time, the escape phenomenon. Hypocalcaemia can occur, particularly in the context of treatment for hypercalcaemia. The dominant safety issue, however, is the malignancy signal identified in the 2012 European review, in which pooled long-term data showed an excess of various cancers with an absolute difference of roughly 0.7 to 2.4 per cent depending on formulation. No mechanism has been established and confounding cannot be excluded, but the finding was consistent enough for the CHMP to conclude that long-term use in osteoporosis was no longer justified. Treatment durations in Europe are now explicitly capped by indication. This entry is educational and does not describe how to use or obtain the medicine.
Regulatory status
| Jurisdiction | Status |
|---|---|
| United Kingdom | Restricted following the EMA Article 31 referral (procedure EMEA/H/A-31/1291), on which the CHMP adopted its opinion on 19 July 2012 and the European Commission decided on 13 February 2013. Nasal spray formulations were withdrawn. Injectable and infusion forms remain authorised only for hypercalcaemia of malignancy, Paget's disease of bone in patients unresponsive to or unsuitable for alternatives (with treatment normally limited to three months), and prevention of acute bone loss from sudden immobilisation (maximum four weeks). Use for osteoporosis is not permitted. |
| United States | FDA-approved. The injection is indicated for Paget's disease of bone, hypercalcaemia and postmenopausal osteoporosis; the nasal spray is indicated for postmenopausal osteoporosis in women more than five years past menopause where alternative therapies are unsuitable. A 2013 advisory committee voted that the benefits of the nasal spray no longer outweighed its risks, but the FDA did not withdraw approval and instead added malignancy information to the labelling. Generic products are available. |
| WADA (sport) | Not named on the WADA Prohibited List. Calcitonin is an antiresorptive calcium-regulating hormone with no established performance-enhancing profile and does not fall within the S2 growth factor provisions. Athletes should verify against the current list. |
Questions
Salmon calcitonin is roughly 40 to 50 times more potent than human calcitonin at the human calcitonin receptor, because sequence differences in the mid-region give it higher affinity and slower dissociation, and it also has a longer plasma half-life. The price of that foreignness is a much greater tendency to provoke neutralising antibodies.
The Article 31 review pooled randomised and post-marketing data and found a higher proportion of cancers in long-term calcitonin users than in controls, with the largest absolute excess (about 2.4 per cent) in the nasal spray data. Since the nasal spray was licensed only for osteoporosis, and the Committee concluded calcitonin should no longer be used for osteoporosis at all, the formulation had no remaining indication.
With continued exposure, the calcium-lowering and antiresorptive effect of calcitonin diminishes over days to weeks. Two processes contribute: downregulation and desensitisation of calcitonin receptors on osteoclasts, and formation of neutralising antibodies against the fish peptide. It is one reason calcitonin was never a satisfactory long-term osteoporosis treatment.
There is some evidence that it reduces pain in acute, recent osteoporotic vertebral compression fracture, and much less evidence for remote or chronic fracture pain. The supporting trials are small, mostly older, and of mixed methodological quality. The proposed central mechanism involving endogenous opioid and serotonergic pathways is plausible but not well established.
Yes, in narrow settings. In Europe the injectable form remains authorised for hypercalcaemia of malignancy, for Paget's disease of bone where alternatives are unsuitable, and for preventing acute bone loss from sudden immobilisation, all with explicit short duration limits. Its rapid onset makes it useful as a bridging agent in acute hypercalcaemia while slower-acting treatments take effect.