Full text of DOI:10.1359/jbmr.2002.17.8.1478

JOURNAL OF BONE AND MINERAL RESEARCH
Volume 17, Number 8, 2002
© 2002 American Society for Bone and Mineral Research
Bioavailability and Biological Efficacy of a New Oral
Formulation of Salmon Calcitonin in Healthy Volunteers*
THIERRY BUCLIN,1,2 MONICA COSMA ROCHAT,1,2 PETER BURCKHARDT,3
4
4
¨
MOISE AZRIA, and MARTINE ATTINGER
ABSTRACT
Salmon calcitonin (SCT) is a well-tolerated peptide drug with a wide therapeutic margin and is administered
parenterally for long-term treatments of bone diseases. Its clinical usefulness would be enhanced by the develop-
ment of an orally active formulation. In this randomized crossover double-blinded phase I trial, controlled by both
a placebo and a parenteral verum, we have tested a new oral formulation of SCT associated with a caprylic acid
derivative as carrier. Eight healthy volunteers received single doses of 400, 800, and 1200 ␮g of SCT orally, a
placebo, and a 10-␮g (50 IU) SCT intravenous infusion. SCT was reliably absorbed from the oral formulation, with
an absolute bioavailability of 0.5–1.4%, depending on the dose. It induced a marked, dose-dependent drop in blood
and urine C-terminal telopeptide of type I collagen (CTX), a sensitive and specific bone resorption marker, with the
effects of 1200 ␮g exceeding those of 10 ␮g intravenously. It also decreased blood calcium and phosphate, and
increased the circulating levels of parathyroid hormone (PTH) and, transiently, the urinary excretion of calcium.
It was well-tolerated, with some subjects presenting mild and transient nausea, abdominal cramps, diarrheic stools,
and headaches. This study shows that oral delivery of SCT is feasible with reproducible absorption and systemic
biological efficacy. Such an oral formulation could facilitate the use of SCT in the treatment of osteoporosis and
other bone diseases. (J Bone Miner Res 2002;17:1478–1485)
Key words: calcitonin, oral administration, intestinal absorption, bone resorption markers, healthy humans
of this treatment was recognized early, its convenience was
limited during some times by the requirement of daily
injections, because the peptide is readily degraded and prac-
tically not absorbed through the gastrointestinal tract.(6–8)
Subsequently, noninjectable formulations using the nasal
and the rectal routes were developed for salmon calcitonin
(SCT), taking advantage of its high affinity for the human
receptor and slow elimination rate, which allows the deliv-
ery of smaller amounts than the human analog.(9–16) Nev-
ertheless, the quest for an orally active formulation re-
mained forceful.(17,18) Considering its administration over
several months or years, its good safety profile, and its wide
therapeutic margin, calcitonin has been regarded as a pro-
totype candidate for the challenge of making a peptide drug
bioavailable through the digestive tract.
INTRODUCTION
ALCITONIN IS used in the management of bone disorders
such as osteoporosis, Paget’s disease, and Su¨deck’s
C
algoneurodystrophia.(1–5) Although the excellent tolerability
*Presented at the 23rd annual meeting of the American Society
for Bone and Mineral Research, October 16, 2001, Phoenix, Ari-
zona, USA.
Dr. Attinger has financial interests in the forms of corporate
appointments and stock options with Novartis. Dr. Azria has fi-
nancial interests in the form of corporate appointments and stock
options with Novartis and has an agreement with Novartis and
Emisphere. Dr. Buclin’s institution (University Hospital of Lau-
sanne) received funds for the conduct of the study. Dr. Burckhardt
has financial interests in the form of stock ownership and serves as
a consultant. He also is a member of the Board of Directors of
Novartis. Dr. Cosma Rochat’s institution (University Hospital of
Lausanne) received funds for the conduct of the study.
Two main pathways have been explored for this pharma-
ceutical development.(17,19,20) Protection of SCT against
1Division of Clinical Pharmacology, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
2Dr. Thierry Buclin and Dr. Monica Cosma Rochat contributed equally in this work.
3Department of Medicine, Service A, University Hospital of Lausanne (CHUV), Lausanne, Switzerland.
4Novartis Pharma International, Basle, Switzerland.
1478

ORAL SALMON CALCITONIN
1479
proteolytic degradation in the intestinal lumen was at- to refrain from strenuous exercise and drug consumption
tempted using acid additives, protease inhibitors, water/oil over the whole study duration and from any alcohol, nico-
emulsions, slow-release and mucoadhesive microparticle tine, caffeine, or calcium-rich food for 2 days before each
formulations, polymer-based hydrogels, or direct conjuga- study day. On study mornings, they had to remain fasted
tion to fatty acids or short polymers. On the other hand, and to note the time of urine emission. They were admitted
amelioration of the mucosal penetration of SCT was sought in the investigation unit and a catheter was inserted in an
using permeation enhancers such as bile acids derivatives, arm vein for repeated blood sampling. They received stan-
acylcarnitine, detergents, phospholipids, fatty acids, or oil dardized meals and beverages from 2 to 24 h after the
emulsions. Various formulations associating SCT with such administration of the test drug (i.e., at 11 a.m., 1 p.m., and
additives have been patented and tested in animals over the 6 p.m.). At the end of the last study period, the medical and
past years,(17,21–24) but to our knowledge, no results have laboratory examinations were repeated. The study protocol,
been published to date regarding the biological efficacy of information sheet, and consent form received approval from
an oral form of SCT in humans, which represents the crucial the Ethics Committee of the Faculty of Medicine in Lau-
outcome for this development. Two small phase I trials for sanne on December 7, 2000.
enteric-coated preparations combining SCT with citric acid
and either taurodeoxycholic acid or laurylcarnitine were
Treatment protocol
reported briefly and showed an average bioavailability of
0.03% and 0.38%, respectively.(25) A lipid-based prepara-
The study followed a five-period randomized placebo-
tion showing encouraging effects in animals(22) was claimed controlled crossover design. It was performed under double-
to enter a phase III trial in osteoporosis patients, but the blind conditions, except for the verum. It compared three
unsuccessful results were never reported in the scientific single oral doses of SCT (400, 800, and 1200 ␮g) with an
literature.(26)
oral placebo and with a verum intravenous infusion of SCT
A new family of low molecular weight carriers, derived (10 ␮g; i.e., 50 IU). The oral formulation consisted of
from N-acylated amino acids, have been developed re- tablets containing 400 ␮g of SCT (Novartis Pharma, Basle,
cently.(27) They are thought to increase selectively the mu- Switzerland) and 225 mg of a caprylic acid derivative as
cosal uptake by inducing conformational changes in the specific carrier,(27) colyophilized from a sodium phosphate-
peptide molecules.(28) While forming noncovalent bonds buffered solution. The oral placebo consisted of matching
with the carrier, the molecules undergo partial unfolding lactose tablets. During the four oral treatment periods, the
and may both relax their shape and expose inner lipophilic subjects received 0, 1, 2, or 3 tablets of the active compound
residues, thus facilitating their transmembrane passage.(29) and, respectively, 3, 2, 1, or 0 placebo tablets, according to
Unlike traditional surfactants and detergents, this class of a preestablished randomization list, with 300 ml of mineral
absorption promoters has a certain specificity for peptides water (Henniez, Henniez, Switzerland). The SCT infusion
and polyaminoglycans and is practically devoid of toxic was prepared with commercial Miacalcic ampoules (50
activity toward the intestinal epithelial cells. During pre- IU/ml; Novartis Pharma) and administered over 1 h through
clinical studies, products of this class have been shown to a catheter in the arm opposite to blood sampling. The
promote the systemic absorption of orally administered SCT subjects had to remain fasting from the evening before until
with an excellent tolerability.
2 h after drug administration.
Considering the obvious therapeutic interest of an oral
formulation of SCT based on this technology, we have
designed this phase I clinical trial to verify that it was
absorbed to a significant extent and produced the biological
Study measurements
Blood samples were drawn at predose time and 15, 30,
and metabolic changes expected in healthy humans, to eval- and 45 minutes and 1, 1.5, 2, 3, 4, 6, 9, 12, and 24 h
uate its absolute bioavailability and to confirm its short-term postdose. They were immediately centrifuged and the
safety and tolerability. In particular, the study aimed to plasma was separated, frozen, and sent in one batch for
compare the antiresorptive activity profiles of oral and in- determination of SCT concentrations by a sensitive and
jected SCT by measuring the blood levels and urine excre- highly specific chemoluminescence-based sandwich immu-
tion of the C-terminal telopeptide of type I collagen (CTX), noassay method, using mouse monoclonal and rabbit poly-
a highly sensitive and specific biological marker of bone clonal antibodies. The assay had a quantification limit of 2.5
resorption.(30)
pg/ml, an intra-assay precision of 6.2%, and an interassay
reproducibility of 16.6%, without cross-reactivity with hu-
man calcitonin. The following biological response markers
were measured at predose time and 30 minutes and 1, 2, 3,
4, 6, 9, 12, and 24 h postdose: blood ionized calcium and
pH, using a specific electrode device (ABL700; Radiometer,
MATERIALS AND METHODS
Study subjects
Eight healthy male volunteers (age, 22–37 years; weight, Copenhagen, Denmark); total serum calcium, phosphate,
65–86 kg) were included in the study after giving their and albumin, using standard colorimetric methods (Syn-
written informed consent. Their good health was assessed chron CX5 analyzer; Beckman Coulter, Fullerton, CA,
by a complete medical examination and standard blood and USA); serum CTX, using a sandwich ELISA kit (Beta-
urine tests, including thyroid and parathyroid hormones Crosslaps; detection limit 0.01 ng/ml, intra- and interday
(PTH) and 25-hydroxyvitamin D3 determinations. They had variability Ͻ5%; Roche Diagnostics, Meylan, France); and

1480
BUCLIN ET AL.
parathyroid hormone (PTH), using a chemoluminescence
immunoassay (detection limit 2 pg/ml, intra- and interday
variability Ͻ7%; Nichols Institute Diagnostics, San Juan
Capistrano, CA, USA). Serum 25-hydroxyvitamin D3 and
osteocalcin were determined in the predose and the 24-h
postdose samples, using, respectively, a radioimmunoassay
(RIA) kit (DiaSorin, Stilwater, MN, USA) and a sandwich
immunoradiometric assay kit (Elsa-Osteo; CIS Bio/
Schering, Gif-sur-Yvette, France). All the urines were saved
in separate collections from morning rise to predose time,
predose to 1.5 h, 1.5–3 h, 3–6 h, 6–9 h, 9–12 h, and 12–24
h postdose. Each collection was timed carefully and
weighted for volume determination, and samples were kept
frozen for determination of calcium, phosphate, creatinine,
and CTX using an ELISA kit (Crosslaps; detection limit 50
ng/ml, intra- and interday variability Ͻ10%; Osteometer,
Copenhagen, Denmark). All measurements were performed
under blinded conditions.
FIG. 1. Plasma SCT concentrations after three oral doses of SCT (Œ,
400 ␮g; , 800 ␮g; F, 1200 ␮g) and after a 1-h intravenous SCT
infusion (ᮀ, 10 ␮g; means Ϯ SDs of log-transformed measurements in
eight volunteers). The dotted lines indicate the average slope used to
extrapolate AUC values to infinity at the lower doses.
Data analysis
RESULTS
The blood measurement data were averaged at each
time according to treatment using geometric averages for
plasma SCT, CTX, and PTH, considering their skewed
distribution. Urinary excretion rates were calculated from
the concentration, volume, and duration of each collec-
tion. The pharmacokinetics of SCT were assessed using
standard noncompartmental calculations under Excel
(version 2000; Microsoft, Redmond, WA, USA): data
examination for the peak concentration Cmax and time to
peak tmax; log-linear regression for the terminal rate
constant ␭ and resulting half-life t1/2 ϭ Log(2)/␭; trape-
zoidal rule with extrapolation to infinity for the area
under the curve (AUC); ratio of dose over AUC for the
apparent systemic clearance CL/F; ratio of CL/F over
rate constant for the apparent distribution volume V/F;
and ratio of oral over intravenous AUCs divided by dose
for the absolute bioavailability F.(31) In addition, a com-
partmental model was fitted to the plasma SCT data using
the population pharmacokinetics software P-Pharm (ver-
sion 1.5; Innaphase, Champs-sur-Marne, France). The
efficacy data (CTX and PTH after log-transformation)
were submitted to an ANOVA for repeated measure-
ments accounting for the factors treatment, subject and
time, and their respective interactions; the significance of
the time-by-treatment interaction was assessed using the
Huynh-Feldt correction for repeated measurements. Post
hoc comparisons of means observed under active treat-
ment versus placebo at corresponding times were per-
formed using the Scheffe´ method under the protection of
the global test for the time-by-treatment effect. Finally,
the maximum percent decrease (PDmax) and the area
under the effect curve (AUEC) were calculated from
log-transformed CTX values reported to baseline and
submitted to an ANOVA along with the pharmacokinetic
parameters to test for a treatment effect. All statistical
computations were performed with the Stata software
(version 6; Stata Corp., College Station, TX, USA).
Parmacokinetics
The plasma concentration profiles of SCT after the three
oral doses and the intravenous infusion are depicted in Fig.
1. Concentrations were detectable up to 0.5–1.5 h after the
dose of 400 ␮g, 1–2 h after 800 ␮g, and 1–4 h after 1200
␮g given orally and were of the same order of magnitude
than those observed after the 10-␮g intravenous infusion.
The pharmacokinetic parameters are summarized in Table
1. The data did not allow a precise characterization of the
terminal rate constant and half-life. Therefore, these param-
eters were estimated only after the highest oral dose and
after the infusion, and the AUCs were estimated after 400
␮g and 800 ␮g were extrapolated to infinity based on the
half-life calculated after 1200 ␮g. The average absolute
bioavailability across all oral doses was 0.8%. It tended to
increase with the dose, reaching 1.4% for 1200 ␮g (p ϭ
0.10). The estimates of apparent clearance and distribution
volume varied conversely. The peak SCT concentration
corrected for dose and the time to peak followed a similar
trend (p ϭ 0.13 and p Ͻ 0.0001, respectively), suggesting
some degree of nonlinearity in the absorption process. An
additional population pharmacokinetic modeling showed
that a one-compartment model with first-order absorption
was appropriate to fit the data; the absorption rate constant
was 2.4 Ϯ 0.5 hϪ1, resulting in an absorption half-life of
0.29 h; the oral bioavailability was 1.37 Ϯ 1.02%; the
absolute clearance was 64 Ϯ 3 liters/h; and the distribution
volume was 16.6 Ϯ 0.8 liters; in accordance with an elim-
ination half-life of 0.18 h. As indicated by this approach, the
absorption would represent a rate-limiting step in the dis-
position of oral SCT.
Markers of bone metabolism
The serum levels and the urinary excretion rates of CTX
are shown in Fig. 2. Both markers reflected a marked

ORAL SALMON CALCITONIN
1481
TABLE 1. NON-COMPARTMENTAL PHARMACOKINETIC AND PHARMACODYNAMIC PARAMETERS OF ORAL AND
INTRAVENOUS SALMON CALCITONIN (SCT).
Dose of SCT:
400 ␮g oral
800 ␮g oral
1200 ␮g oral
10 ␮g intravenous
Pharmacokinetic parameters:
Cmax (pg/mL)
tmax (h)
t1/2 (h)
AUC (pg ⅐ h/mL)
CL/F (L/h)
60 Ϯ 31
0.38 Ϯ 0.13
93 Ϯ 66
0.44 Ϯ 0.12
370 Ϯ 350
0.50 Ϯ 0.13
0.31 Ϯ 0.09
273 Ϯ 287
7889 Ϯ 5436
2994 Ϯ 1657
1.44 Ϯ 1.42
173 Ϯ 37
0.97 Ϯ 0.09
0.28 Ϯ 0.05
158 Ϯ 31
65 Ϯ 12
26.2 Ϯ 5.6
(not evaluable)
31 Ϯ 20
54 Ϯ 41
18442 Ϯ 11554
8191 Ϯ 7019
0.54 Ϯ 0.39
21947 Ϯ 13406
9011 Ϯ 4771
0.41 Ϯ 0.24
V/F (L)
F (%)
(reference 100%)
Pharmacodynamic parameters:
PDmax (%)a
85.1 Ϯ 9.1
16 Ϯ 6
89.5 Ϯ 5.6
17 Ϯ 5
93.7 Ϯ 2.8
30 Ϯ 11
93.3 Ϯ 2.9
23 Ϯ 6
AUEC (Log ⅐ h)b
Means Ϯ Standard Deviations in 8 Volunteers. Cmax: Peak SCT Concentration, tmax: Time to Peak; t1/2: Terminal Half-Life, AUC:
Area Under the SCT Curve, CL/F: Apparent Systemic Clearance; V/F: Apparent Distribution Volume; F: Absolute Bioavailability,
PDmax: Maximum Percent Decrease in Serum CTX, AUEC: Area Under the Curve of Log CTX, Reported to Baseline.
a An average value of 62 Ϯ 10% was observed after placebo.
b An average value of 9 Ϯ 2 Log ⅐ h was observed after placebo.
dose-dependent inhibition of bone resorption after oral as
well as intravenous SCT (p Ͻ 0.0001). The maximum
percent decrease and the AUEC for serum CTX are sum-
marized in Table 1. These efficacy results are in full agree-
ment with the pharmacokinetic data; both the plasma SCT
concentration and the effect profile of the 800-␮g oral dose
fell below those of the 10-␮g intravenous infusion, and
those of the 1200-␮g oral dose reached higher levels, as
shown in Fig. 3. Thus, considering both pharmacokinetic
and pharmacodynamic criteria, the bioavailability of the
oral SCT formulation can be roughly estimated around 1%.
Although the pharmacokinetic profile of oral SCT displayed
a somewhat higher variability compared with that of the
intravenous administration, this had no significant influence
on the variability of the response. Interestingly, both the
1200-␮g oral dose and the 10-␮g infusion of SCT decreased
slightly the serum osteocalcin concentrations at 24 h (from
32 Ϯ 12 ng/ml to 27 Ϯ 9 ng/ml and 27 Ϯ 8 ng/ml,
respectively; p ϭ 0.004).
Biochemical variables
The measurements of other variables also revealed dose-
related effects of oral SCT. They confirmed the approximate
equivalence of the 1200-␮g oral dose and the 10-␮g intra-
venous infusion. Oral SCT decreased to similar extents both
the ionized blood calcium (p ϭ 0.015; Fig. 4) and the total
serum calcium (p ϭ 0.017, not shown). All active doses
exerted a transient calciuric effect (p ϭ 0.002), evident on
the first urine collection (0–1.5 h) and extending over the
second collection (1.5–3 h) for the 1200-␮g dose only; a
slight decrease of calcium excretion was noticed from 9 to
12 h after this dose (Fig. 4). SCT decreased serum phos-
phate between 2 and 6 h compared with placebo (p ϭ 0.015,
FIG. 2. Serum concentrations and urinary excretion rates of CTX
after three oral doses of SCT (Œ, 400 ␮g; , 800 ␮g; and F, 1200 ␮g),
not shown), without consistent effects on phosphaturia (p ϭ
0.2). It did not affect blood pH (p ϭ 0.9), albumin (p ϭ 0.2),
25-hydroxyvitamin D (p ϭ 0.6), or creatinine excretion rate
after a 1-h intravenous SCT infusion (ᮀ, 10 ␮g), and after a placebo
(E, 153, means Ϯ SDs of log-transformed measurements in eight
volunteers). *Significant differences from placebo (p Ͻ 0.05).

1482
BUCLIN ET AL.
FIG. 3. Individual values of
peak SCT concentrations (Cmax),
area under the SCT curve, peak
percent decrease of serum CTX
(PDmax), and AUEC after various
oral doses of SCT (the 10-␮g in-
travenous dose and the placebo).
(p ϭ 0.6). Finally, both the SCT infusion and the 1200-␮g concentration and dose-effect relationships can be observed,
oral dose tended to produce a moderate Ͻ50% increase in
serum PTH levels between 15 minutes and 12 h and 2 and
12 h, respectively (p ϭ 0.08; Fig. 5).
in line with a good reproducibility of the absorption despite
this low bioavailability (Fig. 3). The pharmacokinetic pa-
rameters evaluated after the intravenous infusion are in fair
agreement with values published earlier(32–36); the shorter
half-life and higher systemic clearance found here probably
can be explained by progress in the determination methods,
with increased specificity resulting in lower signal from
cross-reactive metabolites. The lower terminal half-life val-
ues observed after oral administration, compared with those
after intravenous infusion, suggest a slight slow-release
effect of the oral formulation.
Among the study variables, serum CTX represented the
most sensitive biological marker to reflect the rapid and
profound inhibition of bone resorption induced by SCT. The
higher variability observed in plasma SCT levels after oral
administration compared with intravenous administration
did not translate into a proportional variability in the CTX
response. This probably is explained by SCT eliciting a
near-maximal response at the applied dosage range, where
the concentration-effect curve tends to flatten. On the other
hand, serum CTX also displayed some decrease after pla-
cebo, probably related to food intake at breakfast and
lunch.(37) Moreover, bone resorption is known to be affected
by circadian rhythms, which may have influenced the re-
sponse to both SCT and placebo over the follow-up pe-
riod.(38) Urinary CTX excretion rate paralleled the blood
levels, with comparable sensitivity and precision. The re-
quirement of urine collections makes it difficult to repeat
urinary measurement at shorter time intervals, this may
introduce further imprecision (e.g., because of improper
time or volume recording or incomplete bladder voiding).
Safety and tolerability
The study medication caused no serious problem. Alto-
gether, 33 adverse events were recorded on 21/40 study
periods, all of them being scored mild. The most frequent
events were transient nausea and abdominal cramps, which
occurred after 4/8 exposures to 1200 ␮g of oral SCT, 2/8
exposures to 10 ␮g of intravenous infusion, 1/8 exposure to
800 ␮g orally, and 1/8 exposure to 400 ␮g orally. Head-
aches were reported after 3/8 exposures to 10 ␮g intrave-
nously, 2/8 exposures to 1200 ␮g orally, 2/8 exposures to
400 ␮g orally, and 1/8 exposure to 800 ␮g orally. Three
subjects had one or two diarrheic stools after the oral intake
of 1200 ␮g. Neither the measurements of vital signs nor the
safety tests at study completion revealed any clinically
significant abnormality.
DISCUSSION
Our results show that an oral formulation of SCT asso-
ciated with a N-acylated amino acid derivative as carrier is
able to produce all the biological effects of calcitonin in
healthy volunteers. The intestinal absorption of the peptide
remains limited, as indicated by both the pharmacokinetic
and the pharmacodynamic criteria indicating a bioavailabil-
ity of ϳ1%. Thus, ϳ1000 ␮g are required through the oral
route to reproduce the concentrations and the effects of an
intravenous infusion of 10 ␮g (50 IU). Consistent dose- These results are in agreement with several other studies

ORAL SALMON CALCITONIN
1483
FIG. 5. Serum PTH concentrations after three oral doses of SCT (Œ,
400 ␮g; , 800 ␮g; and F, 1200 ␮g) after a 1-h intravenous SCT
infusion (ᮀ, 10 ␮g) and after a placebo (E, means Ϯ SDs) of log-
transformed measurements in eight volunteers. *Significant differences
from placebo (p Ͻ 0.05).
because the placebo did not contain the enhancer but merely
lactose. Finally, the concomitant use of two control treat-
ments, one placebo and one verum (the intravenous SCT
infusion), increases the strength of the evidence of biolog-
ical effectiveness of the oral SCT tested.
Thus, the challenge of making a peptide such as SCT
absorbable through the oral route appears to have been
taken up successfully. The formulation evaluated here
seems to have satisfactory biopharmaceutical characteris-
tics, without relying on sophisticated and costly manufac-
turing techniques. The tolerability of the preparation was
good; it mainly reproduced the mild, transient effects, which
were described after injectable nasal or rectal calcitonin and
which were observed after the intravenous SCT infusion.
The observation of isolated diarrheic stools after the highest
oral dose, and not after the infusion, may suggest a direct
secretory effect of high local SCT concentration on the
intestinal mucosa, as described in animal experiments, or
less probably another mechanism related to the presence of
the carrier.
SCT as a single drug has an established, although limited,
effectiveness in osteoporosis.(3,11,47,48) Peptides like SCT
and PTH analog probably will keep an important place in
the treatment of this condition.(49) Unlike other hormones,
neurotransmitters, or cytokines, the peptidic agents used in
the treatment of bone and mineral disorders have fairly wide
therapeutic margins and satisfactory safety profiles and are
applied over prolonged periods. Thus, the perspective of
administering such drugs through the oral route with reli-
able absorption characteristics is highly attractive.
FIG. 4. Blood ionized calcium and urinary calcium excretion rate
after three oral doses of SCT (Œ, 400 ␮g; , 800 ␮g; and F, 1200 ␮g)
after a 1-h intravenous SCT infusion (ᮀ, 10 ␮g) and after a placebo (E,
means Ϯ SDs of log-transformed measurements in eight volunteers).
*Significant differences from placebo (p Ͻ 0.05).
having shown a marked effect of SCT on CTX or other bone
resorption markers such as urinary pyridinoline, deoxypyr-
idinoline, or hydroxyproline, either in healthy volunteers or
in individuals with osteoporosis.(16,18,30,39–42) Our observa-
tion of a slight decrease in serum osteocalcin after the
highest SCT doses is in line with the concept of coupling
between bone resorption and formation. Although a decline
of this formation marker has been reported regularly in
osteoporosis or Paget patients after several weeks of calci-
tonin treatment, this trend appears detectable in healthy
subjects already after a single administration of SCT.(3)
The performance of other metabolic markers such as
calcemia, calciuria, phosphatemia, and serum PTH to assess
the biological activity of SCT is clearly inferior. However,
these measurements still have their importance to confirm
that the administered preparation exerts the whole array of
known biological effects of calcitonin.(1,16,43–46) In fact, had
it relied only on CTX, this study could not have excluded a
ACKNOWLEDGMENTS
The authors are grateful to Chantal Csajka, Monique
singular effect of the absorption enhancer on this marker, Appenzeller, Anne-Franc¸oise Jacquet, Yannick Batard, Ali

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BUCLIN ET AL.
16. Thamsborg G, Skousgaard SG, Daugaard H, Schifter S,
Kollerup G, Sorensen OH 1993 Acute effects of nasal salmon
calcitonin on calcium and bone metabolism. Calcif Tissue Int
53:232–236.
Maghraoui, Emmanuel Tamche`s, and Philippe Rousso for
their excellent assistance during the study; to Jeroˆme Biol-
laz for his expert supervision of the research; and to the
study volunteers for their collaboration and patience. This
study received financial support from Novartis Pharma In-
ternational, who also provided the study drugs.
17. Lee YH, Sinko PJ 2000 Oral delivery of salmon calcitonin.
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Address reprint requests to:
Thierry Buclin, M.D.
Division of Clinical Pharmacology
University Hospital of Lausanne (CHUV)
Hoˆpital Beaumont 633
CH-1011 Lausanne, Switzerland
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Received in original form November 20, 2001; in revised form
February 13, 2002; accepted March 19, 2002.