9.
Calcitonin
in
the
treatment
of
osteoporosis
Kerry
Siminoski,
MD,
FRCPC;
Robert
G.
Josse,
MD,
FRCPC
Objective:
To
describe
potential
therapeutic
uses
of
calcitonin
in
the
prevention
and
treatment
of
osteoporosis.
Options:
Parenterally
and
intranasally
administered
calcitonin
(eel,
salmon
or
human).
Outcomes:
Fracture,
fracture
pain
and
loss
of
bone
mineral
density
in
osteoporosis;
increased
bone
mass,
prevention
of
fractures,
reduction
of
pain
and
improved
quality
of
life
associated
with
calci-
tonin
treatment.
Evidence:
Relevant
clinical
studies
and
reports
were
examined,
with
an
emphasis
on
recent
randomized,
placebo-controlled
trials.
In
vitro
and
in
vivo
studies
of
osteoclast
activity
were
also
considered.
Values:
Reducing
fractures
and
fracture
pain,
increasing
bone
mineral
density
and
minimizing
side
effects
of
treatment
were
given
a
high
value.
Benefits,
harms
and
costs:
Calcitonin
reduces
acute
pain
associated
with
osteoporotic
fractures
and
has
been
found
useful
in
treating
chronic
back
pain
following
vertebral
fractures
in
spinal
osteo-
porosis.
It
can
prevent
bone
loss
and
may
be
effective
in
preventing
fractures.
Side
effects
are
dose
related
and
generally
mild;
they
include
gastrointestinal,
vascular
and
dermatologic
conditions
that
can
be
treated
symptomatically
or
by
varying
the
dosage.
Side
effects
are
much
rarer
with
nasal
ad-
ministration
than
with
injection.
True
allergic
reactions
are
rare.
Recommendations:
Calcitonin
in
both
intramuscular
and
intranasal
forms
can
reduce
the
pain
of
acute
osteoporotic
vertebral
fractures
and
may
be
effective
in
treating
that
associated
with
chronic
vertebral
osteoporotic
fractures.
Calcitonin
may
also
prevent
postmenopausal
bone
loss
and
in-
crease
bone
density
in
those
with
established
osteoporosis.
Current
evidence
for
long-term
pre-
vention
of
fractures
is
limited
and
does
not
support
the
use
of
calcitonin
as a
first-line
treatment
for
established
osteoporosis.
Most
side
effects
can
be
avoided
with
nasal
administration.
Further
trials
are
needed
to
assess
fracture
prevention
and
effective
dose
ranges
for
treating
pain
and
in-
creasing
bone
mineral
density
and
to
determine
the
long-term
efficacy
of
calcitonin
in
secondary
osteoporosis,
in
premenopausal
women,
in
men
and
in
elderly
people.
Validation:
These
recommendations
were
developed
by
the
Scientific
Advisory
Board
of
the
Osteo-
porosis
Society
of
Canada
at
its
1995
Consensus
Conference.
Sponsors:
Sponsors
of
the
1995
conference
included
the
Dairy
Farmers
of
Canada,
Eli
Lilly
Canada,
Inc.,
Hoffinann-La
Roche
Canada
Limited,
Merck
Frosst
Canada
Inc.
and
Procter
&
Gamble
Phar-
maceuticals
Canada
Inc.
Additional
support
to
assist
with
publication
provided
by
Sandoz
Canada
Inc.
alcitonin,
a
32-amino-acid
polypeptide
discovered
in
1962,
is
produced
in
humans
by
the
parafollicu-
lar
cells
of
the
thyroid
gland.
It
has
an
important
al-
though
as
yet
incompletely
defined
role
in
calcium
homeostasis.
One
of
its
major
physiologic
roles
in
bone
metabolism
is
to
suppress
the
activity
of
osteoclasts,
thereby
decreasing
bone
resorption.
Calcitonin
from
an-
imal
species
has
been
used
for
many
years
in
the
treat-
ment
of
various
metabolic
bone
diseases,
especially
Paget's
disease.
Because
osteoporosis
results
partly
from
an
imbalance
between
rates
of
bone
resorption
and
for-
mation,
calcitonin
has
been
an
obvious
candidate
as
a
therapeutic
agent
for
the
prevention
and
treatment
of
osteoporosis.
Parenterally
administered
calcitonin
and,
more
recently,
intranasal
calcitonin
are
available
in
a
number
of
countries
around
the
world.
The
purpose
of
this
paper
is
to
describe
potential
therapeutic
uses
of
cal-
citonin
in
the
prevention
and
treatment
of
osteoporosis.
Calcitonn
preparations
Several
molecular
forms
of
calcitonin
are
available
for
therapeutic
use.
The
first
commercially
available
calci-
tonin
was
extracted
from
salmon.
This
calcitonin,
as
well
Dr.
Siminoski
is
with
the
Department
of
Medicine,
University
of
Alberta,
Edmonton,
Alta.;
Dr.
Josse
is
a
professor
of
medicine,
Division
of
Endocrinology
and
Medicine,
University
of
Toronto,
and
is
with
the
Metabolic
Bone
Clinic,
St.
Michael's
Hospital,
Toronto,
Ont.
This
statement
was
prepared
at
the
1995
Consensus
Conference
of
the
Osteoporosis
Society
of
Canada.
Reprint
requests
to:
Ms.
Mary
Bowyer,
Osteoporosis
Society
of
Canada,
33
Laird
Dr.,
Toronto
ON
M4G
3S9;
416
696-2663
962
CAN
MED
ASSOC
J
*
1
er
OCT.
1996;
155
(7)
-W
-,--Tlm...,
as
that
extracted
from
other
fish
(e.g.,
eels),
is
more
po-
tent
than
human
calcitonin
and
acts
over
a
longer
pe-
riod.
More
recently,
synthetic
salmon,
human
and
eel
calcitonin
have
become
available.
The
traditional
route
of
administration
has
been
via
subcutaneous
or
intra-
muscular
injection.
Although
injectable
calcitonin
has
proved
to
be
safe,
the
parenteral
route
has
limited
its
ac-
ceptability
to
patients.
Newer
formulations
for
in-
tranasal
administration
have
become
popular
in
some
countries.
Calcitonin
has
also
been
given
rectally,
but
data
on
this
route
of
administration
are
limited.
Treatment
of
fracture
pain
Osteoporotic
vertebral
fractures
may
be
asympto-
matic
and
detected
only
on
radiologic
investigation.
In
many
cases,
however,
vertebral
fractures
can
produce
significant
pain
and
debility,
which
can
persist
for
many
months
following
the
fracture.
Calcitonin
has
been
used
to
treat
pain
associated
with
a
number
of
bone
condi-
tions,
including
Paget's
disease
and
metastatic
bone
dis-
ease,
as
well
as
for
the
pain
from
vertebral
fractures
that
occur
as
a
result
of
osteoporosis.
In
each
condition,
pain
relief
begins
within
the
first
several
days
following
initia-
tion
of
therapy,
in
many
cases
before
significant
alter-
ation
in
bone
metabolism
can
be
demonstrated.
This
suggests
that
the
pain-relieving
action
of
calcitonin
is
not
primarily
a
result
of
its
modulation
of
bone
turnover.
Although
the
exact
mechanism
of
acute
pain
relief
is
not
known,
calcitonin
is
thought
to
act,
at
least
in
part,
by
stimulating
the
endogenous
opioid
system.
A
number
of
early,
uncontrolled
studies
reported
a
role
for
calcitonin
in
relief
of
the
pain
of
acute
osteo-
porotic
vertebral
fracture.IA
The
natural
course
of
pain
following
such
fractures
is
gradual
improvement
over
several
weeks
to
months.
Thus
the
benefits
demon-
strated
in
such
uncontrolled
studies
are
only
suggestive
of
a
possible
therapeutic
effect.
Comparison
with
placebo
is
necessary
to
demonstrate
the
efficacy
of
any
agent
used
for
fracture
pain
relief.
At
least
three
ran-
domized,
placebo-controlled
studies
have
been
reported
using
calcitonin
in
acute
vertebral
fracture
cases.5'7
As-
sessment
of
efficacy
has
been
based
on
*
reports
by
patients
of
spontaneous
pain
at
rest
or
in
various
positions,
*
reports
by
patients
of
induced
pain,
*
physician
assessment
of
the
degree
of
patient
pain,
*
the
degree
of
limitation
of
activities
and
*
doses
of
analgesics
used
by
patients.
By
these
criteria,
calcitonin
has
been
shown
to
produce
significant
alleviation
of
the
acute
pain
that
occurs
as
a
re-
sult
of
osteoporotic
vertebral
fracture.
The
effects
of
pain
reduction
persist
for
at
least
the
first
month
of
administra-
tion.
Only
salmon
calcitonin
has
been
used
in
controlled
trials,
although
data
suggest
that
all
forms
by
all
routes
may
be
active.
One
study
demonstrated
a
beneficial
effect
in
glucocorticoid-induced
osteoporotic
vertebral
fractures.6
Chronic
back
pain
can
develop
following
vertebral
fractures
in
spinal
osteoporosis.
The
mechanisms
are
un-
clear
but
may
include
persistent
injury
to
the
vertebrae,
degenerative
changes
subsequent
to
the
fracture
and
pain
originating
from
paraspinal
tissues
resulting
from
abnor-
mal
anatomical
positioning
and
spinal
malalignment.
One
randomized,
placebo-controlled
study8
has
demon-
strated
that
calcitonin
may
provide
pain
relief
in
this
chronic
state.
Pain
relief
may
occur
if
calcitonin
is
insti-
tuted
anytime
within
the
first
year
after
fracture,
al-
though
data
suggest
that
the
benefit
is
greater
the
earlier
the
drug
is
administered.
Pain
relief
continues
for
at
least
4
months
of
administration.
In
the
reported
study,
syn-
thetic
human
calcitonin
was
administered
subcutaneously
at
doses
of
0.125
or
0.25
mg
three
times
per
week.8
Most
studies
of
pain
relief
in
osteoporotic
vertebral
fractures
have
assessed
only
postmenopausal
women.
One
report7
included
a
small
number
of
male
patients,
but
no
separate
analysis
is
available
to
determine
whether
their
response
rates
are
different
from
those
of
postmenopausal
women.
Data
are
also
limited
on
the
use
of
calcitonin
for
relief
of
pain
following
fracture
at
nonvertebral
sites
or
in
secondary
osteoporosis.
Role
of
calcitonin
in
the
prevention
of
fractures
The
effects
of
calcitonin
on
bone
can
be
considered
in
three
areas:
biochemical
markers
of
bone
turnover,
bone
density
and
fracture
rate.
Biochemical
markers
of
bone
turnover
In-vitro
and
in-vivo
studies
show
that
calcitonin
is
effec-
tive
in
inhibiting
osteoclast
activity,
thereby
reducing
bone
resorption.
The
biochemical
markers of
bone
resorption,
such
as
urinary
hydroxyproline
and
pyrodinolines,
are
de-
creased.
However,
demonstration
of
reduction
in
the
bio-
chemical
parameters
of
bone
turnover
in
the
short
term
does
not
necessarily
indicate
long-term
improvements
in
bone
mass
or
reduction
in
fracture
prevalence.
Bone
density
A
large
number
of
uncontrolled
studies,
often
of
short
duration,
using
different
preparations
of
calcitonin
have
shown
that
bone
density
increases
significantly
during
the
course
of
observation.
However,
as
randomized,
placebo-controlled
studies
are
considered
necessary
to
assess
this
effect
of
calcitonin,
only
this
type
of
study
will
be
considered
further.
The
majority
of
such
studies
have
demonstrated
greater
bone
density
in
calcitonin-treated
patients
compared
with
controlsY24
In
some
cases,
con-
trols
were
given
only
placebo,
in
others,
both
treatment
and
control
groups
received
calcium
or
calcium
and
vita-
CAN
MED
ASSOC
J
*
OCT.
1,
1996;
155
(7)
963
min
D
supplements.
Differences
in
bone
density
have
been
demonstrated
as
early
as
3
months
following
insti-
tution
of
calcitonin
treatment,
and
benefits
have
been
reported
to
persist
for
up
to
3
years
and,
in
one
small
study,
5
years.
In
some
studies,
bone
density
did
not
in-
crease;
it
was
merely
maintained,
compared
with
a
loss
of
bone
density
in
the
control
group.
In
other
studies,
bone
density
increased
by
as
much
as
5%
to
10%
over
2
years
of
therapy.
This
is
similar
to
the
increase
in
bone
density
seen
with
the
bisphosphonates,
another
class
of
drugs
that
inhibits
bone
resorption.
This
implies
that
the
increase
in
bone
density
associ-
ated
with
calcitonin
treatment
is
another
example
of
im-
provement
secondary
to
filling
in
the
resorption
space.
Because
calcitonin
is
primarily
an
antiresorptive
agent,
it
may
be
most
effective
in
situations
where
bone
resorp-
tion
is
increased.
In
one
well-conducted
study,25
calci-
tonin
was
most
effective
in
preventing
further
bone
loss
and
modestly
increasing
bone
mass
in
patients
with
in-
creased
bone
turnover,
compared
with
a
low
turnover
group
in
whom
little
significant
effect
of
calcitonin
was
observed.
Only
one
controlled
study2'
has
included
male
patients,
but
no
separate
analysis
is
available
to
deter-
mine
whether
their
response
differs
from
that
of
post-
menopausal
women.
The
same
report
studied
glucocor-
ticoid-induced
osteoporosis
and
demonstrated
a
ben-
eficial
effect
of
calcitonin
on
bone
density.
Controlled
data
on
the
use
of
calcitonin
in
other
forms
of
secondary
osteoporosis
are
limited.
Several
studies,'
1"2
mostly
of
short
duration
(1
to
2
years),
have
demonstrated
the
efficacy
of
both
parenteral
and
intranasal
calcitonin
in
preventing
bone
loss
in
the
early
postmenopausal
period.
On
the
basis
of
these
data,
it
has
been
suggested
that
calcitonin
might
be
a
useful
alternative
for
those
who
cannot
or
will
not
take
estro-
gen.
Beneficial
effects
on
bone
density
have
been
demon-
strated
for
virtually
all
forms
of
calcitonin
over
a
wide
range
of
dosages,
although
formal
dose-ranging
and
dose-response
studies
are
limited.
Intermittent
dosing
schedules
have
also
been
studied
and
appear
to
be
effec-
tive,'5
but
long-term
confirmatory
evidence
is
required.
Long-term
effects
of
calcitonin
on
bone
density
are
not
known,
as
most
controlled
studies
report
data
for
only
1
to
2
years
of
therapy;
the
longest
controlled
study
is
3
years
of
treatment.20
Uncontrolled
studies
have
suggested
that
bone
density
either
reaches
a
plateau
or
may
actually
begin
to
decrease
after
several
years
of
calcitonin
therapy.
Antibodies
to
calcitonin,
particularly
to
fish
calci-
tonin,
develop
in
a
significant
proportion
of
patients
re-
ceiving
long-term
treatment.
There
is
some
concern
that
these
antibodies
may
diminish
the
efficacy
of
cal-
citonin,
but
the
extent
to
which
they
interfere
with
cal-
citonin
action
remains
unresolved.
Measurement
of
cal-
citonin
antibodies
is
a
research
tool
and
is
not
indicated
for
patient
monitoring
or
treatment
decisions.
Fracture
rate
Several
early,
controlled
studies
designed
to
look
at
changes
in
bone
density
in
response
to
calcitonin
ther-
apy
also
reported
on
fracture
incidence.
The
relative
risks
calculated
from
these
data
are
contradictory.
How-
ever,
none
of
these
studies
was
designed
to
look
at
frac-
ture
rates,
and
patient
numbers
were
too
small
to
pro-
duce
statistically
significant
risk
assessments.
There
have
been
at
least
two
controlled,
randomized
studies,2426
both
of
2 years'
duration,
that
have
produced
statistically
sig-
nificant
reductions
in
vertebral
fracture
rates
in
calci-
tonin-treated
postmenopausal
women.
One
of
these24
also
found
a
decrease
at
all
fracture
sites.
In
one
study,26
patients
were
given
salmon
calcitonin
intramuscularly
for
only
10
days
per
month
at
a
dose
of
100
IU/d,
along
with
a
calcium
supplement.
The
other
study24
gave
50,
100
or
200
IU/d
of
salmon
calcitonin
in-
tranasally
along
with
calcium.
The
design
of
this
study24
is
better,
and
it
shows
a
convincing
small
but
statistically
significant
sustained
increase
in
lumbar
vertebral
bone
mineral
density
in
elderly
postmenopausal
women
with
established
osteoporosis.
In
addition,
despite
the
small
number
of
patients
(particularly
as
only
the
200
IU/d
dose
was
consistently
efficacious),
there
was
a
significant
reduction
in
the
prevalence
of
fractures.
This
study24
was
not
specifically
powered
to
look
at
fracture
rates;
thus,
it
was
fortuitous
that
the
authors
were
able
to
detect
a
significant
difference
among
the
groups
given
the
small
sample
size.
Despite
the
fact
that
initial
fracture
rates
were
low
(fewer
than
10%
to
15%
of
participants
had
vertebral
fractures
at
baseline),
the
small
number
of
patients
and
other
methodological
problems,
this
trial
demonstrates
a
statistically
signifi-
cant
increase
in
bone
mineral
density
resulting
from
200
IU/d
of
calcitonin
administered
nasally
over
2
years.
Data
on
hip
fractures
from
prospective,
controlled
studies
are
limited.
A
single
case-control
study27
of
post-
menopausal
women
demonstrated
a
significant
reduc-
tion
in
hip
fractures
in
calcitonin-treated
patients
com-
pared
with
controls.
Although
suggestive,
this
finding
is
limited
by
the
inherent
selection
biases
and
weaknesses
of
case-control
methods.
There
are
no
control
data
on
fracture
risk
in
men,
in
premenopausal
women
or
in
sec-
ondary
osteoporosis.
There
is
no
information
on
whether
apparent
benefits
are
sustained
beyond
2
years
of
calcitonin
treatment.
Side
effects
Side
effects
in
patients
receiving
intramuscular
or
subcutaneous
calcitonin
are
dose
related
and
generally
inconvenient
rather
than
serious,
but
can
occur
in
up
to
80%
of
patients
on
high
doses.
The
most
common
side
effects
are
gastrointestinal
and
consist
of
anorexia,
nau-
sea,
vomiting,
a
metallic
taste
or,
rarely,
diarrhea.
Vascu-
964
CAN
MED
ASSOC
j
*
1
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OCT.
1996;
155
(7)
lar
phenomena,
such
as
flushing
or
shivering,
are
the
next
most
common,
followed
by
dermnatologic
changes,
including
a
local
rash
at
the
injection
site,
a
generalized
rash
and
pruritus.
These
skin
changes
are
usually
not
immunologic
in
origin.
True
allergic
reactions,
consist-
ing
of
urticaria
and
anaphylaxis
are
rare.
In
the
past,
a
test
dose
of
calcitonin
with
medical
monitoring
was
rec-
ommended
to
detect
individuals
with
an
acute
allergic
reaction.
This
approach
is
probably
not
necessary
be-
cause
of
the
rarity
of
anaphylaxis
and
because
anaphy-
laxis
may
occur
only
after
multiple
doses.
Headache
and
diuresis
may
also
occur
in
some
patients.
Side
effects
of
nasal
calcitonin
are
similar
to
those
oc-
curring
with
the
injected
drug,
but
are
much
less
com-
mon.
Local
skin
reactions
do
not
occur
as
they
are
se-
quelae
of
the
injection
method,
but
nasal
irritation
may
occur.
Anaphylaxis
has
not
been
reported.
Specific
side
effects
may
be
treated
with
medications
that
relieve
the
symptoms.
Alternatively,
because
most
side
effects
are
dose
related
and
decrease
in
severity
with
duration
of
use,
the
calcitonin
dose
may
be
reduced
and
gradually
increased
as
tolerated.
Even
with
these
mea-
sures,
up
to
a
third
of
people
using
injected
calcitonin
will
discontinue
therapy.
Only
a
small
fraction
will
stop
using
the
much
better
tolerated
nasal
calcitonin.
Conclusions
*
Calcitonin
can
be
an
effective
therapy
for
the
pain
of
acute
osteoporotic
vertebral
fractures
and
should
be
instituted
as
early
as
possible.
Both
intramuscular
and
intranasal
forms
are
effective.
Therapy
should
be
adjusted
according
to
response
and
may
be
effective
for
at
least
1
month.
*
Calcitonin
may
provide
relief
of
back
pain
in
patients
with
chronic
vertebral
osteoporotic
fractures
and
can
provide
benefit
for
several
months
in
those
who
respond.
*
Calcitonin
given
either
parenterally
or
intranasally
has
been
shown
to
prevent
bone
loss
in
the
early
postmenopausal
period
and
in
women
with
estab-
lished
osteoporosis.
*
The
evidence
for
efficacy
of
calcitonin
for
long-term
prevention
of
fractures
is
limited;
therefore,
it
is
not
possible
to
provide
an
accurate
estimate
of
the
de-
gree
of
fracture
risk
reduction.
Although
data
suggest
that
calcitonin
can
reduce
fracture
incidence,
current
evidence
does
not
provide
strong
support
for
the
use
of
calcitonin
as
a
first-line
treatment
for
established
osteoporosis.
*
Calcitonin
is
a
safe
drug,
but
it
can
produce
a
wide
range
of
usually
mild
side
effects
in
a
significant
propor-
tion
of
patients
when
injected.
Side
effects
are
much
less
common
with
the
nasal
route
of
administration.
*
Further
randomized,
controlled
clinical
trials
of
cal-
citonin
therapy
-particularly
assessing
fracture
pre-
vention
and
effective
dose
ranges
for
treating
pain
and
improving
bone
mineral
density
-
are
necessary
to
delineate
more
fully
the
role
of
calcitonin
in
os-
teoporosis
therapy.
Studies
are
also
needed
to
deter-
mine
specifically
the
long-term
efficacy
of
calcitonin
in
secondary
osteoporosis,
in
premenopausal
women,
in
men
and
in
elderly
people.
1.
Wallach
S,
Cohn
SA,
Atkins
HL
et
al.
Effect
of
salmon
calcitonin
on
skeletal
mass
in
osteoporosis.
Curr
Tber
Res
1977;22:556-72.
2.
Franceschini
R,
Bottaro
P,
Panopoulos
C,
Messina
V.
Long-term
treatment
with
salmon
calcitonin
in
postmenopausal
osteoporosis.
Curr
Ther
Res
1983;34:795-800.
3.
Zorzin
L,
Capone
M.
Post-menopausal
osteoporosis:
therapeutic
and
side
ef-
fects
of
different
calcitonins.
Curr
Ther
Res
1984;36:473-82.
4.
Palmieri
GMA,
PitcockJA,
Brown
P
et
al.
Effect
of
calcitonin
and
vitamin
D
in
osteoporosis.
Cakif
Tissue
Int
1989;45:137-41.
5.
Lyritis
GP,
Tsakalakos
N,
Magiasis
B
et
al.
Analgesic
effect
of
salmon
calci-
tonin
in
osteoporotic
vertebral
fractures:
a
double-blind
placebo-controlled
clinical
study.
Cakif
Tissue
Int
1991;49:369-72.
6.
Ringe
JD,
Welzel
D.
Salmon
calcitonin
in
the
therapy
of
corticoid-induced
osteoporosis.
EurJ
Clin
Pbarmacol
1987;33:35-9.
7.
Pun
KK,
Chan
LW.
Analgesic
effect
of
intranasal
salmon
calcitonin
in
the
treatment
of
osteoporotic
vertebral
fractures.
Clin
Ther
1989;1
1:205-9.
8.
Ljunghall
S,
Giirdsell
P,
Johnell
0
et
al.
Synthetic
human
calcitonin
in
post-
menopausal
osteoporosis:
a
placebo-controlled,
double-blind
study.
Cakif
Tis-
sue
Int
1991;49:17-9.
9.
Gennari
C,
Chlerichetti
SM,
Bigazzi
S
et
al.
Comparative
effects
on
bone
mineral
content
of
calcium
and
calcium
plus
salmon
calcitonin
given
in
two
different
regimens
in
postmenopausal
osteoporosis.
Curr
Ther
Res
1985;
38:455-64.
10.
Mazzuoli
GF,
Passeri
M,
Gennari
C
et
al.
Effects
of
salmon
calcitonin
in
postmenopausal
osteoporosis:
a
controlled
double-blind
clinical
study.
Cakif
Tissue
Int
1986;38:3-8.
11.
Reginster
JY,
Denis
D,
Albert
A
et
al.
1-Year
controlled
randomised
trial
of
prevention
of
early
postmenopausal
bone
loss
by
intranasal
calcitonin.
Lancet
1987;2:1481-3.
12.
MacIntyre
I,
Stevenson
JC,
Whitehead
MI
et
al:
Calcitonin
for
prevention
of
postmenopausal
bone
loss.
Lancet
1988;1:900-2.
13.
Overgaard
K,
Riis
BJ,
Christiansen
C
et
al.
Effect
of
salcatonin
given
in-
tranasally
on
early
postmenopausal
bone
loss.
BMJ'
1989;299:477-9.
14.
Overgaard
K,
Riis
BJ,
Christiansen
C
et
al.
Nasal
calcitonin
for
treatment
of
established
osteoporosis.
Clin
Endocrinol 1989;30:435-42.
15.
Overgaard
K,
Hansen
MvA,
Nielsen
VH
et
al.
Discontinuous
calcitonin
treat-
ment
of
established
osteoporosis
-
effects
of
withdrawal
of
treatment.
Am
J
Med
1990;89:1-6.
16.
Thamsborg
G,
Storm
TL,
Sykulski
R
et
al.
Effect
of
different
doses
of
nasal
salmon
calcitonin
on
bone
mass.
Cakif
Tissue
Int
1991;48:302-7.
17.
Fioretti
P,
Gambacciani
M,
Taponeco
F
et
al:
Effects
of
continuous
and
cyclic
nasal
calcitonin
administration
in
ovariectomized
women.
Maturitas
1992;15:225-32.
18.
Gennari
C,
Agnusdei
D,
Montagnani
M
et
al.
An
effective
regimen
of
in-
tranasal
salmon
calcitonin
in
early
postmenopausal
bone
loss.
Cakif
Tissue
Int
1992;50:381-3.
19.
Meschia
M,
Brincat
M,
Barbacini
P
et
al.
A
clinical
trial
on
the
effects
of
a
combination
of
elcatonin
(carbocalcitonin)
and
conjugated
estrogens
on
ver-
tebral
bone
mass
in
early
postmenopausal
women.
Calcif
Tissue
Int
1993;53:17-20.
20.
Reginster
JY,
Denis
D,
Deroisy
R
et
al.
Long-term
(three
years)
prevention
of
trabecular
postmenopausal
bone
loss
with
low-dose
intermittent
nasal
salmon
calcitonin.
J
Bone
Miner
Res
1994;9:69-73.
21.
Luengo
M,
Pons
F,
Martinez
de
Osaba
MJ
et
al.
Prevention
of
further
bone
mass
loss
by
nasal
calcitonin
in
patients
on
long
term
glucocorticoid
therapy
for
asthma:
a
two
year
follow
up
study.
Thorax
1994;49:1099-102.
22.
Overgaard
K.
Effect
of
intranasal
salmon
calcitonin
therapy
on
bone
mass
and
bone
turnover
in
early
postmenopausal
women:
a
dose-response
study.
Cakif
Tissue
Int
1994;55:82-6.
23.
Reginster
JY,
Deroisy
R,
Lecart
MP
et
al.
A
double-blind,
placebo-con-
trolled,
dose-finding
trial
of
intermittent
nasal
salmon
calcitonin
for
preven-
tion
of
postmenopausal
lumbar
spine
bone
loss.
Am
J
Med
1995;98:452-8.
24.
Overgaard
K,
Hansen
MA,
Jensen
SB
et
al.
Effect
of
salcatonin
given
in-
tranasally
on
bone
mass
and
fracture
rates
in
established
osteoporosis:
a
dose-response
study.
BMJ
1992;305:556-61.
25.
Civitelli
R,
Gonnelli
S,
Zacchei
F
et
al.
Bone
turnover
in
postmenopausal
os-
teoporosis.
Effect
of
calcitonin
treatment.
J
Clin
Invest
1988;82:1268-74.
26.
Rico
H,
Hernandez
ER,
Revilla
M
et
al.
Salmon
calcitonin
reduces
vertebral
fracture
rate
in
postmenopausal
crush
fracture
syndrome.
Bout
Miuer
1992;16:131-8.
27.
Kanis
J,
Johnell
0,
Gullberg
B
et
al.
Evidence
for
efficacy
of
drugs
affecting
bone
metabolism
in
preventing
hip
fracture.
BMJ'
1992;305:1
124-8.
CAN
MED
ASSOC
J
*
OCT.
1,
1996;
155
(7)
965
