Calcitonin: A useful old friend

600

Review Article

Akash Srinivasan*, Felyx K Wong*, Dimitrios Karponis

Imperial College London School of Medicine, UK

*contributed equally

Background

Calcitonin, in various preparations, has been used to

treat metabolic bone disease for over forty years since its

discovery in 1961 as a blood-calcium lowering hormone

Salmon calcitonin, in particular, has been effective in

treating postmenopausal osteoporosis, Paget’s disease and

hypercalcaemia

2,3

. Due to its ability to inhibit osteoclast

activity, calcitonin reduces the risk of vertebral re-fracture,

and it is also a powerful analgesic agent with proven efficacy

in managing acute back pain caused by recent vertebral

compression fractures

4,5

By 1992, world sales of therapeutic calcitonin had

exceeded 900 million US dollars

. However, the rise of

bisphosphonates pushed calcitonin to the side; since the

1960s, etidronate has been utilised as a therapy, primarily

for hypercalcaemia and Paget’s disease, and in 1995,

alendronate received approval by the US Food and Drug

Administration (FDA) for the treatment of postmenopausal

osteoporosis

. Since 2007, zoledronic acid has also been

licensed for the treatment of postmenopausal osteoporosis,

following evidence on its beneficial effects on bone mineral

density (BMD), bone metabolism markers and a reduction

in vertebral, hip and other fractures

. Multiple trials have

demonstrated superior efficacy in bisphosphonates and

alternative treatment options, which have consequently led

to decreased use of calcitonin.

Although bisphosphonates possess multiple effects

and are potent medications, there are significant adverse

effects associated with long-term use, such as atypical

femoral fractures and osteonecrosis of the jaw

. Therefore,

it is interesting to see the extent to which these drugs

have superseded calcitonin. This review aims to explore

the reasons behind the decline of calcitonin and discuss its

potential role in the years to come.

Biochemistry and pharmacology

Calcitonin is a single-chain polypeptide hormone which is

made up of 32 amino acids. An N-terminal disulfide bridge

between the cysteine residues at positions 1 and 7 create

a 7-amino acid ring structure and there is also a C-terminal

amidated proline

. The physiological effects of calcitonin are

Abstract

Calcitonin regulates blood calcium levels and possesses certain clinically useful anti-fracture properties. Specifically,

it reduces vertebral fractures in postmenopausal osteoporotic women significantly compared to a placebo. Nevertheless,

the use of calcitonin has declined over the years and salmon calcitonin is no longer the first-line treatment for many

of its indications. Commercial calcitonin only exists in intranasal or injectable preparations, which are less preferable

for patients. Efficacy of a potential oral formulation has been under investigation but achieving adequate bioavailability

remains a conundrum and the latest phase III trials have not shown promising evidence justifying its use. Associations with

cancer have also derailed this treatment option. Furthermore, the rise of bisphosphonates and, more recently, monoclonal

antibodies (such as denosumab), has revolutionised the treatment of osteoporotic fractures. Therefore, we are posed with

an interesting question: is calcitonin a treatment of the past? This review aims to explore the reasons behind this paradigm

shift and outline the potential role of calcitonin in the management of fractures and other conditions in the years to come.

Keywords: Analgesia, Calcitonin, Formulations, Fracture, Osteoporosis

The authors have no conflict of interest.

Corresponding author: Dimitrios Karponis, South Kensington, London, SW7

2AZ, UK

E-mail: dimitriskarponis@gmail.com

Edited by: G. Lyritis

Accepted 11 March 2020

Journal of Musculoskeletal

and Neuronal Interactions

Published under Creative Common License CC BY-NC-SA 4.0 (Attribution-Non Commercial-ShareAlike)

J Musculoskelet Neuronal Interact 2020; 20(4):600-609

601http://www.ismni.org

A. Srinivasan et al.: Remembering calcitonin

known to occur through receptor-mediated processes, and

interactions involving the N-terminal ring and the C-terminus

appear to be involved in receptor binding and signal

transduction

9,10

In humans, calcitonin is secreted by the para-follicular

or C cells of the thyroid gland in response to an increase in

serum calcium concentration

. Primarily, calcitonin targets

the bone, where it profoundly inhibits osteoclast action and

bone resorption. Actively resorbing osteoclasts secrete acid

and acid hydrolases via their ruffled borders to degrade bone.

Calcitonin promotes the internalisation of the osteoclasts’

ruffled border proteins into intracellular vesicles, thereby

thwarting acid release and preventing the demineralisation

of bone matrix

. Calcitonin also acts via the kidneys, where

it reduces the reabsorption of calcium, along with sodium,

potassium, chloride and phosphate. Furthermore, the

hormone works on the central nervous system to induce

analgesia, stomach acid secretion and anorexia

The exact mechanism behind the analgesic effects of

calcitonin remains elusive, yet several theories have been

proposed. A 2016 study on rats discovered that calcitonin

decreases the number of serotonin transporters, whilst

increasing the expression of thalamic serotonin receptors

Other studies have proposed that nerve injuries activate a

calcitonin-dependent signal, which reduces transcription

of the sodium channel in the neurons of the dorsal root

ganglion

Calcitonin has been studied in numerous species

including pig, rat, salmon and eel. Subtle structural

differences massively affect their respective affinities for

calcitonin receptors. For example, salmon calcitonin has

a greater affinity to calcitonin receptors in all species,

compared to mammalian calcitonin and therefore, its higher

potency combined with its longer half-life has made salmon

calcitonin the standard form used to treat bone disorders

9,12

Although clinical resistance from circulating antibodies

can form against non-human calcitonin, the use of human

calcitonin is limited due to its susceptibility to precipitating

as insoluble fibrils

Salmon calcitonin has been commercially available in

an injectable form and as a nasal spray, but developing an

oral formulation of a peptide hormone, which can survive

gastric enzymatic digestion and subsequently penetrate

the intestinal mucosa, has been a challenge

. However, oral

delivery of calcitonin has been shown to be feasible by linking

salmon calcitonin with various additives, including permeation

enhancers (e.g. a caprylic acid derivative), enzyme inhibitors

and particulate systems

2,15,16

The history of calcitonin

Parenteral calcitonin was the first FDA approved

formulation, available as an intramuscular or subcutaneous

injection. However, its use was associated with poor

patient compliance and tolerability due to its extensive

side effects, the most notable of which was gastrointestinal

disturbance

17-20

. Numerous studies reported nausea, loss of

appetite, abdominal pain and diarrhoea. In addition, patients

also experienced flushing in the face and peripheries; local

inflammatory reactions were also common at the site of

administration

18,19

. Data on the efficacy of the injectable

formulation is scarce. In a retrospective cohort study

conducted by Kanis et al., a significant risk reduction in

hip fractures (RR: 0.69, 95% CI: 0.51-0.92) was observed

following a year of daily calcitonin injections, compared to

control

. However, a similar magnitude of risk reduction was

observed in patients receiving daily calcium supplementation

(RR: 0.75, 95% CI: 0.60-0.94). It is important to note that,

due to its extensive side effect profile, the use of injectable

calcitonin has been mostly replaced by the later developed

intranasal formulation.

The intranasal formulation has been the preferred method

of administration over the parenteral route due to multiple

factors. Firstly, it is more convenient and less invasive

for the patient. Moreover, common side effects resulting

from salmon calcitonin administration, such as nausea and

vomiting, occur less frequently in studies using the intranasal

formulation

4,22

. Collectively, these factors promote better

drug tolerability and patient compliance. However, the nasal

formulation has been reported to have lower bioavailability

and slower absorption than the injectable formulation

. Mild

nasal symptoms have also been observed in multiple studies,

including nasal irritation, rhinitis and rhinorrhoea

4,18,22

One of the important studies which led to the 1995 FDA

approval of intranasal salmon calcitonin was the PROOF

study (Prevent Recurrence of Osteoporotic Fracture)

The PROOF study was an international, multi-centre trial

which demonstrated that a 5-year daily 200IU dose of

intranasal calcitonin, along with daily vitamin D and calcium

supplementation, was able to reduce vertebral fracture

risk by 36% compared to placebo in postmenopausal

women living with osteoporosis. A significant but modest

improvement in lumbar BMD was seen in all treatment arms

(100 IU, 200 IU, and 400 IU), while serum bone resorption

markers were also significantly reduced. This was the first

large-scale, prospective study looking into the anti-fracture

efficacy of calcitonin. Prior to this, studies demonstrating

salmon calcitonin’s anti-fracture properties were mostly

retrospective or prospective with small sample sizes

21,24-26

Interestingly, the efficacy of intranasal calcitonin was not

dose-dependent. Patients receiving the daily 200 IU dose

were able to benefit from a greater vertebral fracture risk

reduction than patients on the daily 400 IU and 100 IU

regimens. It is important to acknowledge that the PROOF study

has been criticised for its high dropout rate of 59% by the end

of the 5-year follow up. Although some of the main findings

from this study, including its potential in increasing lumbar

spine BMD and suppression of serum resorption markers,

were consistent with the literature, evidence surrounding

nasal calcitonin’s vertebral anti-fracture efficacy have been

conflicting

24,26-30

. Additionally, the effect of nasal calcitonin

on non-vertebral fracture risk and BMD is unclear

31, 32

. Aside

from its effects on the vertebrae, nasal calcitonin has been

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A. Srinivasan et al.: Remembering calcitonin

shown to have a significant analgesic effect during the early

stages of treating distal radius fractures

Oral calcitonin has raised interest as a result of a few

factors. Firstly, bisphosphonates have received increasing

levels of concern around their long-term, albeit rare, side

effects, including osteonecrosis of the jaw and atypical

femoral fractures

34,35

. This, therefore, renewed the interests

in alternative therapies, including older treatment options

such as calcitonin. Secondly, intranasal and injectable

salmon calcitonin have been associated with suboptimal

patient compliance

. Thus, a potentially more convenient

and accepting method of delivery was explored. However,

due to the peptide nature of calcitonin, achieving adequate

bioavailability from the oral route has been the main challenge

to tackle to date

At the time of composing this review, evidence on oral

calcitonin is limited and data from the latest phase III

trials have not shown promising results, to the best of our

knowledge. The most recent phase III trial, conducted by

Henriksen et al., investigated the anti-fracture efficacy of

oral salmon calcitonin in 4665 postmenopausal women

over 3 years and is the only study hitherto to directly

measure the anti-fracture efficacy of the oral formulation

Achieving adequate bioavailability was a challenge and

pharmacokinetic analysis demonstrated suboptimal

drug exposure in subjects who were administered

calcitonin. Overall, daily oral salmon calcitonin (0.8

mg/d) with calcium and vitamin D supplementation did not

significantly alter new vertebral fracture and non-vertebral

fracture incidence when compared to control (p=0.94). No

significant differences in cumulative fracture risk were

seen between the treatment and control groups across

the 36-month study period. However, participants in the

treatment arm had a statistically longer duration between

baseline and the time of first hip fracture compared to

placebo. The increase in lumbar spine BMD following

oral calcitonin treatment was significantly greater in

the treatment group than placebo (treatment: 1.02%,

control: 0.18%, p<0.0001). Two studies conducted by

Binkley et al. have demonstrated significant but mild

improvement in lumbar spine BMD improvement and

moderate suppression of bone resorption markers

38,39

Anti-fracture efficacy was not assessed in these trials.

Firstly, the ORACAL trial was a phase III study which

showed that daily 0.2 mg oral formulation over 48 weeks

induced a significantly greater improvement in lumbar

spine BMD than the intranasal formulation (p=0.027) and

placebo (p=0.010) groups. Yet, it is important to note

that the absolute differences between the change in BMD

of the oral, intranasal and placebo arms were modest

(1.5%±3.2%, 0.78%±2.9%, 0.5%±3.2%, respectively).

Similarly, the second and more recent trial conducted by

Binkley et al. demonstrated a significant yet mild effect

on lumbar spine BMD (1.03%, p<0.001) following 54-

Table 1. Trials on the anti-fracture efficacy and analgesic effects of intranasal and oral calcitonin.

Reference N Intervention Outcome

Chestnut et al.

(2000)

1255

(511 completed

full 5-year

follow up)

Daily nasal salmon

calcitonin (100, 200

or 400 IU) vs placebo

over 5 years

Daily 200 IU nasal calcitonin significantly reduced vertebral fracture risk.

The 100 IU nasal calcitonin group experienced significantly fewer non-

vertebral fractures compared to placebo.

All dosages significantly increased vertebral BMD compared to placebo.

Significant reductions in bone resorption markers were observed in 200 IU

and 400 IU groups.

Henriksen et al.

(2016)

4665

Daily 0.8mg oral

salmon calcitonin

vs placebo over 36

months

Oral salmon calcitonin did not significantly reduce vertebral and non-vertebral

fractures risk compared to placebo.

The treatment group experienced a significantly greater increase in lumbar

spine BMD than placebo but not in total hip or femoral neck BMD.

Bone resorption markers were significantly lower in oral calcitonin arm than

placebo arm at 12 and 24 months but not at 36 months.

Lyritis et al.

(1991)

Daily calcitonin 100 IU

vs placebo injections

for osteoporotic

vertebral fractures,

over 14 days

Calcitonin 100IU yielded significant reductions in pain (p<0.001) compared

to placebo. These were apparent as early as day 2 of the treatment period.

Urinary hydroxyproline and urinary calcium were significantly lower in the

calcitonin group.

Lyritis et al.

(1999)

Daily 200 IU calcitonin

suppositories vs

placebo over 28 days

Daily calcitonin suppositories demonstrated significant analgesic efficacy

on VAS scores compared to placebo in patients with recent osteoporotic

vertebral fractures.

Karponis et al.

(2015)

Daily 200 IU

intranasal calcitonin

vs placebo over 3

months

Nasal calcitonin demonstrates a statistically significant analgesic efficacy

after distal radius fractures when compared to placebo.

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A. Srinivasan et al.: Remembering calcitonin

week administration of daily 0.2mg recombinant salmon

calcitonin. At non-vertebral sites, changes in BMD at

the hip, femoral neck and trochanter sites were not

statistically different between oral, nasal calcitonin and

placebo groups in the ORACAL trial. At non-vertebral sites,

Henriksen et al. observed a reduction in hip and femoral

neck BMD in both treatment and placebo groups, but the

reduction was greater in the placebo group. In all studies,

a significant decrease in bone resorption markers was

observed, including C-terminal telopeptides of collagen

types I, II (CTX-I, CTX-II respectively) and N-terminal

cross-linked telopeptide of type I collagen (NTx-I)

37-39

. In

the ORACAL study, a significantly greater reduction in

CTx-I was reported in the oral calcitonin group than the

nasal calcitonin group. Henriksen et al. demonstrated that

bone resorption markers in the oral calcitonin group were

significantly lower than placebo at 6, 12 and 24 months,

but not at 36 months. Whether differences in biochemistry

translate to clinical significance, though, is a different

question and, frankly, the one that should be asked.

To date, most studies have been conducted on

postmenopausal women and very few have looked into

calcitonin’s therapeutic efficacy in other patient populations.

A trial conducted by Trovas et al. assessed the efficacy of

daily 200IU nasal calcitonin in 28 males with idiopathic

osteoporosis over 12 months. Nasal calcitonin was able to

significantly increase vertebral BMD compared to placebo

(mean ± standard error of the mean (SEM): 7.1±1.7%

and 2.4±1.5%, respectively, p<0.05). However, similar

improvements in BMD were not observed in the femoral

neck, trochanter and ward’s triangle following calcitonin

administration. Bone resorption markers, including CTX-1,

NTX-1 and urinary deoxypyridinoline, were also suppressed

and the reduction was significantly greater compared to

placebo. This study was not powered to analyse nasal

calcitonin’s anti-fracture efficacy

In the management of corticosteroid-induced

osteoporosis, a Cochrane review conducted by Cranney et al.

(including 9 trials) demonstrated that calcitonin was effective

in improving vertebral BMD at 12 months, with a weighted

mean difference of 3.2% (95% CI: 0.3 to 6.1) compared to

placebo. However, no significant difference was observed

at 24 months. Similar results were observed at the distal

radius, where calcitonin exerted a significant improvement in

BMD compared to placebo at 6 months only. No statistically

significant difference in BMD was observed at the femoral

neck compared to placebo. Additionally, no significant

difference in relative risk for vertebral and non-vertebral

fractures was observed in the treatment groups when

compared to placebo

. Table 1 summarizes key findings

from trials on the efficacy of calcitonin.

Current Indications

In the British National Formulary (BNF), calcitonin is

indicated for use in hypercalcaemia of malignancy, Paget’s

disease of bone, and the prevention of acute bone loss due

to sudden immobility. However, it is contraindicated in

hypocalcaemia, and factors such as heart failure, a history

of allergies and the risk of malignancy need to be taken

into account.

Although calcitonin is not approved by the European

Medicines Agency (EMA) for the treatment of postmenopausal

osteoporosis, it is FDA-approved for managing patients

who are at least 5 years postmenopausal and when the

alternatives are contraindicated. This was largely based on

the PROOF study in 2000 which showed a 30% reduction

in vertebral fracture occurrence in participants with prior

vertebral fractures

. However, due to meta-analyses

reporting a potential, albeit non-definitive, link between

salmon calcitonin and malignancy, it is no longer considered

to be the first-line treatment and should only be used

when the alternatives are contraindicated

44-46

. Calcitonin

may still be preferred for acute osteoporotic fractures as

several studies have observed significant analgesic effects

in the acute setting

33,42,43,46

. In this instance, calcitonin is

recommended for use until the pain resolves, at which point

it should be substituted with a more effective long-term drug.

Calcitonin is EMA and FDA-approved in the treatment of

hypercalcaemic emergencies. It is used due to its fast-acting

calcium-lowering effect which is useful when calcium levels

need to be lowered rapidly. After rehydrating the patient with

saline, calcitonin is co-administered with a bisphosphonate

and other calcium-lowering drugs such as loop diuretics.

The osteoclast-inhibiting effect of calcitonin administration

typically fades after 24-48 hours, but this coincides with

when bisphosphonates’ activity increases; as a result,

co-administration produces a rapid fall in calcium due to

calcitonin, and a sustained decrease over a few days from the

bisphosphonate.

For Paget’s disease of bone, calcitonin is authorised by

the EMA for short-term use and it is the FDA-approved

second-line treatment which should be administrated

when the treatment of choice, zoledronic acid, is not

tolerated or prompt surgery on the bone affected by the

disease is necessary. A study involving 85 participants

found that in the initial months of salmon calcitonin

therapy for Paget’s disease, the main markers of bone

remodelling and turnover (alkaline phosphatase and

urine hydroxyproline) decreased by approximately 50%.

However, 22 of these patients eventually returned to pre-

treatment levels despite continued treatment, and 19 of

those 22 had high titres of anti-calcitonin antibodies

This development of tolerance makes calcitonin a less

viable long-term option in the treatment of Paget’s disease

compared to bisphosphonates, which are not vulnerable to

antibodies. When administering calcitonin, serum alkaline

phosphatase needs to be measured every 3 to 6 months

until it normalises, after which it can be measured every 6

months; if levels rise again, antibody formation should be

suspected.

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A. Srinivasan et al.: Remembering calcitonin

Competitors in the treatment of postmenopausal

osteoporosis

In comparison to calcitonin, the literature surrounding the

anti-fracture efficacy of bisphosphonates has demonstrated

more promising data. Bisphosphonates are pyrophosphate

analogues, which exert their therapeutic effect by attaching

to bone. Active resorption of these areas of bone leads

to osteoclast inhibition via intracellular pathways

48,49

Alendronate and risedronate are the two most commonly

used bisphosphonates for postmenopausal osteoporosis

in the UK. Due to the long half-life of bisphosphonates,

convenient extended-interval dosing regimens, such as once

weekly or once monthly options, are available on the market

and some patient populations may also be eligible to undergo

drug holidays

. Numerous studies have demonstrated anti-

fracture efficacy in bisphosphonate use at both vertebral and

non-vertebral sites

51-54

. Specifically, the Fracture Intervention

Trial (FIT) highlighted that a daily alendronate regimen (5

mg/d for first 24 months, followed by 10 mg/d until 36

months) was able to induce a significant 50% reduction

in vertebral fractures and 30% reduction in wrist and hip

fractures in postmenopausal women with osteoporosis with

at least one previous vertebral fracture

. Furthermore,

femoral neck and lumbar spine BMD were also increased by

4.1% and 6.2%, respectively, throughout the study.

In the 3-year Vertebral Efficacy with Risedronate Therapy

(VERT) trial, Risedronate (5mg/d) was able to reduce

fracture incidence at both vertebral and non-vertebral sites

by 41 % (95% CI: 18%-58%) and 39% (95% CI: 6%-61%),

respectively, compared to placebo. Significant improvements

in BMD were observed at the lumbar spine (5.4%), femoral

neck (1.6%) and trochanter (3.3%) compared to placebo

(1.1%, -1.2%, -0.7%, respectively)

. In the Hip Intervention

Program (HIP) study, McClung et al. demonstrated that daily

risedronate over 3 years was able to significantly lower hip

fracture risk in elderly female patients with pre-diagnosed

osteoporosis, compared to placebo. (RR: 0.6; 95% CI:0.4 to

0.9; P=0.009)

Zoledronic acid is available as a convenient, once-

yearly IV infusion which may be used in cases where

oral bisphosphonates are contraindicated. In the Health

Outcomes and Reduced Incidence with Zoledronic Acid

Once Yearly (HORIZON) Pivotal Fracture Trial, annual

administration of zoledronic acid over 3-years demonstrated

both vertebral and hip anti-fracture efficacy when compared

to placebo (RR: 0.30; 95% CI: 0.24-0.38, HR: 0.59 95%

CI: 0.42-0.83, respectively)

. Additionally, in the HORIZON

Recurrent Fracture Trial, it was able to lower re-fracture

incidence in patients with previous hip fractures (HR:0.65

95% CI 0.50-0.84)

Ibandronate has been shown to exhibit vertebral anti-

fracture efficacy compared to placebo

but there is a lack of

strong evidence justifying its use for hip and non-vertebral

fractures. The BONE study (Ibandronate Osteoporosis

Vertebral Fracture Trial in North America and Europe)

was a 3-year trial conducted on 2946 postmenopausal

women which demonstrated that oral daily (2.5 mg/d) and

intermittent ibandronate (20 mg every other day for 12 doses

every 3 months) were able to reduce vertebral fracture rates

by 62% (p=0.0001) and 50% (p=0.0006), respectively,

compared to placebo. Significant improvements in vertebral

and hip BMD were also observed

Evidence directly comparing the efficacy of

bisphosphonates with calcitonin is limited. A study which

directly compared alendronate with salmon calcitonin

demonstrated a significantly greater increase in lumbar

spine (p<0.001), trochanter (p<0.001) and femoral neck

BMD (p<0.001) in patients who were administered the

bisphosphonate compared to salmon calcitonin over 12

months

. Moreover, a significantly greater reduction in

bone resorption markers within the alendronate group

was observed compared to calcitonin following 12 months

administration (p<0.001).

Denosumab, a fully human monoclonal antibody that

inhibits RANKL, is not regarded as the standard first-line

treatment for postmenopausal osteoporosis

. It has been

shown to be very powerful at countering bone resorption,

reducing fracture rates, increasing BMD and reducing serum

bone resorption markers

59,60

. Notably, the FREEDOM study

(Fracture Reduction Evaluation of Denosumab in Osteoporosis

Every 6 Months) was an international, multi-centre trial

which compared the efficacy of denosumab against placebo

in 7868 women with postmenopausal osteoporosis over

3 years

. The study showed that denosumab was able to

significantly reduce vertebral (RR: 0.32 95% CI: 0.26-

0.41) and hip (hazard ratio (HR): 0.60 95% CI: 0.37-0.97)

fracture risk, increase lumbar and hip BMD and suppress

bone resorption markers. An extension of the trial allowed

the monitoring of an additional 7 years for 4550 participants

from the FREEDOM study which demonstrated the long-

term maintenance of low fracture incidence and continued

rise in vertebral and non-vertebral BMD

. Yet, denosumab

discontinuation is associated with ‘rebound’ bone resorption

and anti-resorptive agents are often prescribed following

withdrawal to minimise this effect

Unlike the aforementioned anti-resorptive agents,

different “anabolic” options are also available on the market,

including teriparatide (PTH analogue) and abaloparatide

(PTHrP analogue). PTH has two contrasting functions on bone

turnover. Despite its net effect of bone resorption during

continuous administration, it promotes bone formation when

delivered intermittently

. In the UK, teriparatide is indicated

for the treatment for postmenopausal osteoporosis and in

males at high risk of fractures and corticosteroid-induced

osteoporosis. The use of abaloparatide is approved by the

FDA for the management of postmenopausal osteoporosis in

the US. However, evidence surrounding its use was deemed

insufficient by the EMA in 2017. In general, anabolic agents

are not first-line for the treatment of osteoporosis, owing to a

plethora of factors, such as the greater cost and inconvenient

administration (subcutaneous injection) compared to most

bisphosphonates

. Intriguingly, treatment withdrawal

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A. Srinivasan et al.: Remembering calcitonin

often results in a progressive decline in BMD which requires

management by anti-resorptive agents; this further limits

the use of anabolic agents

Teriparatide has been shown in numerous studies to

possess anti-fracture efficacy at vertebral and non-vertebral

sites

65-67

. Moreover, the Fracture Prevention Trial was an

international, multi-centre randomized control trial which

demonstrated that a daily regimen of 20 μg or 40 μg injection

over 21 months considerably reduced new vertebral fracture

risk by 65% (RR: 0.35 95%CI: 0.22-0.55) and 69% (RR:

0.31 95%CI: 0.19-0.50) compared to placebo, respectively

Non-vertebral fracture RR in the 20 μg and 40 μg arms were

0.47 (95%CI: 0.25-0.88) and 0.46 (95%CI: 0.25-0.861),

respectively. Daily 20 μg and 40 μg teriparatide were able

to induce a dose-dependent and statistically significant

increase in BMD measured at multiple sites including

the lumbar spine, hip and femoral neck. Studies directly

comparing teriparatide and calcitonin have shown a greater

increase in lumbar BMD in patients treated with teriparatide

compared to salmon calcitonin

68 -70

. However, data comparing

their efficacy on femoral neck and total hip BMD data has

been inconsistent. Specifically, trials have shown an increase

in serum bone formation markers including bone-specific

alkaline phosphatase and osteocalcin in participants taking

teriparatide but not in the calcitonin group

68 -70

. However, it is

important to question the external validity of these studies,

which were mostly conducted on Asian populations and

hence, a clinical benefit remains equivocal when generalising

these findings to other populations.

Discussion

The decline in the use of calcitonin can be attributed to a

variety of causes. There are issues intrinsic to the drug itself,

including an association with cancer, and the lack of a widely-

available oral formulation

2,4

. Additionally, there are extrinsic

factors: primarily, the development of alternative drugs with

greater efficacy.

Firstly, there is the potential risk of malignancy associated

with calcitonin use. This was first brought to attention

by the PROOF trial of nasal salmon calcitonin, where the

results showed a higher risk of cancer in the active group

(8.9%) compared to the placebo group (5.1%), with basal

cell carcinomas being the major finding

. At the time, no

action was taken by the FDA because the age and race of

the participants were confounding factors, but the potential

association was flagged up again after phase III trials for

an oral formulation of calcitonin (SMC021) which reported

cases of prostate cancer

71,72

. In addition to these findings, a

1994 study demonstrated a biological route through which

calcitonin might stimulate the growth of prostate cancer

cells

. Since then, the EMA commissioned a committee

to review all of the salmon calcitonin studies and, in July

2012, stated that salmon calcitonin should no longer be

recommended as a treatment option for postmenopausal

osteoporosis, citing an increased malignancy risk as one of

the paramount reasons. In March 2013, an advisory panel

to the FDA also recommended that calcitonin should not

be indicated for postmenopausal osteoporosis because the

safety risk outweighed the fracture reduction. Although the

FDA did not implement this recommendation, all calcitonin

nasal spray products were withdrawn by Health Canada in

October 2013 and two months later, the Taiwan FDA followed

suit. Furthermore, a case-control study involving 28222

osteoporotic patients in Taiwan found that using a calcitonin

nasal spray in women significantly elevated the risk of liver

cancer, although the risk of breast cancer was reduced

Another reason for the decline in use is that salmon

calcitonin carries significant side-effects, many of which

are related to the gastrointestinal tract such as abdominal

pain, diarrhoea, nausea and vomiting in addition to

arthralgia, musculoskeletal pain and flushing. Studies

investigating the short-term and long-term side-effects

of calcitonin have found that the unwanted effects of the

nasal spray preparation were a lot milder and had a lower

incidence compared to the subcutaneous injectable form of

calcitonin

. However, there were some side-effects specific

to the nasal spray including nasal irritation, sneezing and

rhinitis. As previously mentioned, randomised control

trials involving oral calcitonin found it to be well-tolerated

in general but it was still associated with hot flushes and

gastrointestinal symptoms like nausea and dyspepsia. In the

ORACAL trial, a higher incidence of nausea and dyspepsia

was reported in participants who took the oral calcitonin

than the nasal spray group

One of the most important factors which diverted

healthcare professionals away from the use of calcitonin

was the lack of strong evidence justifying its use, along

with the simultaneous presence of other treatment options

which demonstrated more promising data showing superior

efficacy in increasing multifocal BMD and anti-fracture

efficacy. Whilst the PROOF study was able to illustrate

calcitonin’s anti-fracture efficacy, many other studies did not

show consistent results. In most studies, the fracture rate

was either too low to allow meaningful statistical analysis

or that statistical analysis did not show a significant change

in vertebral fracture rates from calcitonin use. Although

calcitonin has been shown in various trials to increase lumbar

spine BMD and decrease bone resorption markers, including

CTX-I and CTX-II, the clinical utility of using BMD and serum

bone resorption markers in predicting fracture risks have

been questioned

75-77

Future direction

In the future, it is likely that calcitonin will continue to be

used in combination with bisphosphonates for the treatment

of emergency hypercalcaemia and hypercalcaemia of

malignancy due to its rapid action. It is unlikely that calcitonin

will become the first-line treatment for postmenopausal

osteoporotic fractures or Paget’s disease, mainly due to the

proven greater efficacy of bisphosphonates. However, its

606http://www.ismni.org

A. Srinivasan et al.: Remembering calcitonin

powerful analgesic effect should not be overlooked and if a

safe oral formulation that can achieve adequate bioavailability

is found, which would potentially be more beneficial and

acceptable to patients than the nasal spray, then there could

be renewed interest in this drug.

The efficacy of calcitonin in treating acute pain associated

with fractures has already been discussed, but calcitonin

may also be a useful alternative in the treatment of acute

and chronic neuropathic pain with recent studies having been

conducted to look at the potential mechanisms behind this.

This benefit of calcitonin has previously been demonstrated

in the treatment of phantom limb pain where a double-

blinded crossover study showed efficacy in the early post-

operative period

. Additionally, a case report by Visser et al.

illuminated a patient’s recovery from post-herpetic neuralgia

after being administered calcitonin following the failure of

traditional analgesics, and a 2011 case series highlighted

the role of calcitonin in treating acute neuropathic pain

associated with spinal cord injury

79,80

. Other reports which

have indicated potential uses of calcitonin in neuropathic pain

include diabetic neuropathy, lumbar spinal canal stenosis,

reflex sympathetic dystrophy, post-operative pain and

trigeminal neuralgia

Finally, in addition to calcitonin’s effects on reducing bone

resorption, a 2005 study found that an oral form of salmon

calcitonin significantly reduced the urinary excretion of CTx-II,

suggesting that it could decrease the degradation of cartilage

and act as a treatment for osteoarthritis

. Furthermore,

calcitonin has been shown to reduce the levels of rheumatoid

factor and interleukin-1b in patients with rheumatoid arthritis,

but ancillary work is necessary at this stage to establish it

in the armamentarium of anti-rheumatic medications

83,84

This is another example of how successfully creating a viable

oral formulation of calcitonin could be key to the future of

the drug, although achieving adequate concentrations in the

joints of interest may be another challenge.

Conclusion

Since its discovery by Douglas Harold Copp, calcitonin

has been a useful treatment for various metabolic bone

diseases. However, similar to many other medications, it has

been derailed by associations with cancer and superseded

by newer and more potent alternatives. There will still be a

role for calcitonin when patients are unsuitable candidates

for first-line therapies. Furthermore, the development of

an oral formulation could herald a new interest in the drug.

Although calcitonin will be used less for its original purpose

of increasing BMD and reducing fracture risk, its unique

analgesic efficacy means that there may still be a future for

this old friend.

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