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Abstract:
Introduction: Ibadronic acid and intranasal calcitonin have
recently gained popularity in India in the treatment of
osteoporosis and there is no study to compare their clinical
efficacy in Indian set up. This study was, therefore,
designed to compare directly the effects of intranasal
calcitonin and IV Ibandronic acid on BMD as well as
subjective pain perception when used for treatment of
low backache with osteoporosis in postmenopausal women in Indian
setup.
Material and Methods: One hundred thirty two postmenopausal
women presenting to Orthopaedics OPD, JJ Hospital having a T
score less than -2.5 SD on DEXA were included in the study.
These subjects were randomized into two groups, one receiving
Calcitonin spray 200IU daily and other Ibadronic acid 3 mg at 3
monthly interval .Subjects were assessed for BMD and pain
perception using DEXA Scan and Visual Analogue score
respectively at 6 and 12 months.
Observations & Results: Women treated with IV ibandronic acid
achieved significantly greater increases in BMD than
did those treated with calcitonin .The improvement in pain
perception was similar in both the groups.
Discussion: This randomized prospective trial with
clinically relevant doses of these drugs provides important data
for clinicians who treat postmenopausal women with
osteoporosis. The changes in BMD observed in this trial are
consistent with the published data for the treatment
effect of each drug.
J.Orthopaedics 2010;7(2)e9
Keywords:
Osteoporosis; Calcitonin; Ibandronic acid
Introduction:
Osteoporosis is one of the common orthopaedic ailments
encountered in clinical practice which chiefly affects women in
the postmenopausal age. Several therapies are now available for
treatment of osteoporosis in this group. Hormonal
treatment with Estrogen has a positive effect on bone
mineral density (BMD), and also provides relief of
postmenopausal symptoms. However many women are unwilling
to take estrogen due to concerns about breast cancer or
unwanted side effects (1). The nonestrogen therapies
used for treatment of osteoporosis include calcitonin,
given either by the subcutaneous or intranasal
routes, and bisphosphonates, such as Oral Alendronate,
Residronate, oral and intravenous Ibandronic acid and IV
zolendronic acid.
In various studies conducted so far, both intranasal calcitonin
and IV Ibandronic acid both have been reported to be
associated with increases in BMD (2,3,4,5). In the independent
studies, the increases in BMD reported with
Ibandronic acid, in general, are greater than those reported
with calcitonin. However a direct comparison is necessary
to adequately understand the relative efficacy of
these two therapies. This study was,
therefore, designed to compare directly the effects of
intranasal calcitonin and IV Ibandronic acid on BMD
as well as subjective pain perception when used for
treatment of low backache with osteoporosis in postmenopausal
women in Indian setup.
Materials
and Methods:
This prospective, randomized study was conducted at Department
of Orthopaedics, Grant Medical College & Sir JJ Group of
Hospitals, Mumbai. The recruitment of study subjects was done
from August to October 2008. Two hundred and thirty
postmenopausal women of age group 60 to 70 years presenting to
Orthopaedics OPD with complaints of low backache were screened
with peripheral bone mineral densitometer at the heel. One
hundred and ninety women who were having a T score of less than
-2.5 were subjected to central dual-energy x-ray absorptiometry
(DEXA) .One hundred and sixty four subjects having a T score
less than -2.5 SD at the lumbar spine, femoral neck and
trochanter on DEXA were considered eligible for the study. Out
of these one hundred and fifty patients were willing for follow
up and gave informed consent for participation in the study.
Patients were excluded for any of the following:
active rheumatoid arthritis, disorders of bone
mineralization, untreated hyperthyroidism, recent systemic
estrogen therapy, hypercortisolism, or use of drugs
known to alter bone or calcium metabolism. Secondary
causes of osteoporosis were ruled out by including only those
subjects who had normal Serum Calcium, Phosphorus and Alkaline
Phosphatase levels.
After exclusion one hundred and thirty two were enrolled into
the study. Baseline information was collected, which included
current age, age of attaining menopause, total calcium intake
and measurement of low back pain perception by subjects using
Visual Analogue Score. Visual analogue scoring for pain was done
at 6 month and 12 month intervals and the patients were asked to
avoid any NSAID medication at least 48 hours prior to the follow
up visit. Subjects were randomly allocated to intranasal
Calcitonin therapy and IV Ibandronic acid therapy groups by
random number table.
Calcitonin was distributed to patients in the original
packaging. Administration and storage of the drugs
were performed in accordance with the recommendations supplied
by the drug’s manufacturer. Patients assigned to
calcitonin were instructed to administer one 200-IU
dose (one spray) intranasally each day, alternating
nostrils daily. As this therapy was given on OPD basis,
compliance was ensured by asking the patient to bring empty
vials of the spray at the end of the month.
Ibandronic acid group received intravenous Ibandronic acid 3 mg
at 3 monthly intervals. All the doses were given under medical
supervision over 30secs and then patients were observed for next
1 hour for any adverse drug reaction.
The daily intake of calcium of all the subjects was calculated
by 24 hrs recall method using Nutritive Value of Indian
Foods(ICMR) as Standard. Both the groups received an additional
1000mg of elemental calcium and 800IU of vitamin D3 daily during
the study span. The mean improvement in BMD and Pain perception
was calculated for both groups at 6 months and one year interval
and the difference in the two groups was analyzed by statistical
analysis. Data on safety and tolerability of the drugs was also
collected.
Statistical analysis
: Statistical analyses were performed with the SPSS version 16
statistical package. Baseline characteristics were
compared between treatment groups with t tests
(continuous data). Tests comparing the treatment
groups were declared significant at the 0.05 level.
Paired t tests were used for within treatment
comparisons to baseline. Analyses of end points at
intermediate time points were performed in a similar
manner.
An intention-to-treat approach was used in the analyses of BMD
and pain perception outcomes. That is, all patients
who had at least one dose of therapy, a baseline
measurement, and at least one post randomization observation
were included in the analysis. In this analysis, in the
event of missing data, the last post randomization
observation was carried forward to subsequent time
points.
Observations & Results:
Subjects
The characteristics of each treatment group were similar at
baseline (Table 1 ).
The women ranged in age from 60-70 yr, with a mean
age of 65.9 yr. The mean BMD at the lumbar spine, femoral neck
and trochanter at baseline corresponded to T-scores
of -2.8,-2.9 and -2.92, respectively. The mean compliance with
study medication was 88% with ibandronic acid and
94% with calcitonin.
BMD
Significantly greater increases in BMD were seen in the group
treated with ibandronic acid compared with the group
treated with calcitonin at the lumbar spine (P
< 0.001), femoral neck (P < 0.001), and
trochanter (P < 0.001) at 6 months and this increase was
sustained till follow up visit at 12 months .
Subjective Perception of Pain
The mean Visual Analogue Score for pain perception was 7.8 for
all subjects at baseline. At 6 monthly and 12 monthly follow up,
the mean score of Calcitonin group was relatively higher but
this association was not statistically significant. (p >0.05).
There was no significant decrease in mean scores in the 6 to 12
month interval in each group.
Safety and tolerance
None of the patients experienced serious adverse drug reactions,
while minor side effects were seen in both the groups. The most
common complaint of the patients on calcitonin was nasal
irritation experienced by 7 patients, followed by rhinitis in
two patients one of whom also had a single episode of epistaxis.
While in the ibandronic acid group the most common complaint was
local injection site reaction seen in 10 subjects which usually
resolved within an hour, two of the patients reported back after
few hours with complaints of flu like symptoms who were admitted
and treated symptomatically. No symptoms of dyspepsia were seen
as with the oral preparations of ibandronate.
Discussion :
Ibadronic acid and intranasal calcitonin have recently gained
popularity in India in the treatment of osteoporosis and there
is no study to compare their clinical efficacy in Indian set up.
This randomized prospective trial with clinically
relevant doses of these drugs provides important data for
clinicians who treat postmenopausal women with
osteoporosis. In this trial, treatment with ibadronic
acid produced significantly greater increases in BMD
than did intranasal calcitonin over 12 months.
The changes in BMD observed in this trial are
consistent with the published data for the treatment effect
of each drug. Previous studies with ibandronic acid have
shown 1-yr increases in BMD at the spine and hip of a
magnitude similar to those seen in this trial (2,
3). However, the
absolute magnitudes of the changes in BMD demonstrated
with calcitonin in this study are slightly lower than
those seen in other studies. Although the amounts of
calcium and vitamin D used in this study are representative
of doses commonly recommended for patients with
osteoporosis, different results may have been
demonstrated if calcium and vitamin D had not been
used.
This study was designed to ensure optimal conditions for the
use of intranasal calcitonin. The intranasal calcitonin
preparation used in this study was purchased from a
wholesale firm that dispenses calcitonin to
pharmacies and was not altered in any way. In
addition, individuals were instructed about use of the
intranasal spray according to the manufacturer’s
prescribing information , and bottles were changed
every month. Good compliance with intranasal
calcitonin was demonstrated in this 1-yr trial. Thus,
noncompliance does not seem to be an explanation for
differences in BMD change between drugs. Another feature
of this study was the use of a central BMD from the same
center throughout the study to ensure comparability of the BMD
data.
There are several strengths of this study. First, women who
participated in the study were at least 5 yr post
menopause and had low BMD (T-score <-2.5) but did not
have a prevalent vertebral fracture or history of hip
fracture. Women who were less than 5 yr postmenopause were not
included consistent with the prescribing information
for intranasal calcitonin .Women similar to the women
randomized into this study are often encountered in
clinical practice (i.e. an older woman with
low bone mass but no previous fracture)
Tolerability was assessed in this trial by examining the
percentage of patients reporting any side effects.
The percentage of patients reporting any side effects
was similar for all treatment groups indicating that both
ibandronic acid and intranasal calcitonin are
generally well tolerated. Eight patients who received
ibandronic acid dropped out from the study after 6 months in
comparison to four patients from the calcitonin group three of
whom dropped out at the seventh month while one after nine
months interval. This difference indicates towards a better
acceptance of the Calcitonin preparation by the subjects.
However, this number is too small to draw statistically
significant interpretation.
Conclusion:
In conclusion, this randomized trial comparing intranasal
calcitonin and IV ibandronic acid in
postmenopausal women with osteoporosis demonstrated that
women treated with IV ibandronic acid achieved
significantly greater increases in BMD than did those
treated with calcitonin at the lumbar spine, the femoral neck
and trochanter at 12 months. The improvement in pain perception
was similar in both the groups at 6 months as well as 12 month
assessment. The acceptance of the calcitonin spray was slightly
more than the IV infusion of ibandronic acid.
Table 1: Baseline Characteristics of Study Subjects
|
Characteristic |
Intranasal Calcitonin (n=68) |
IV Ibadronic Acid(n=68) |
P Value |
|
Age(yr)*
Years since menopause (yr)
Calcium intake (mg/day)**
Pain perception (VAS)
PA lumbar spine, T-score
Femoral neck, T-score
Trochanter, T-score |
66.6 ± 2.5
17.5 ± 3.4
622 ± 223
7.7±0.9
-2.84 ± 0.18
-2.91 ± 0.3
-2.92±0.28 |
65.1±2.1
16.9 ± 4.2
646 ± 292
7.8 ± 0.6
-2.76 ± 0.20
-2.89 ± 0.22
-2.94±0.31 |
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05
>0.05 |
*As noted from Voting ID cards
** Calculated by 24 hrs recall method using Nutritive Value of
Indian Foods(ICMR) as Standard
Table 2 : Improvement in Visual Analogue Score of Study Subjects
|
Time Interval |
Visual Analogue Score for Low Backache |
P Value |
|
Intranasal Calcitonin (n=68) (Mean ± SD) |
IV Ibadronic Acid(n=68) (Mean ± SD) |
|
Baseline
6 months
12 months |
7.7 ± 0.9
4.1 ± 0.3
3.8 ± 0.9 |
7.8 ± 0.6
3.9 ± 0.4
3.6 ± 0.5 |
>0.05
>0.05
>0.05 |
Table 3: BMD Improvement in Study subjects
|
Site |
Percentage improvement in T Score |
|
Intranasal Calcitonin (n=68) Mean ( 95% CI) |
P Value |
IV Ibadronic Acid(n=68)
Mean ( 95% CI) |
P Value |
|
6 months |
1 year |
<0.05
<0.05
<0.05 |
6 months |
1 year |
<0.05
<0.05
<0.05 |
|
Lumbar Spine
Femoral neck
Trochanter |
0.8(0.72-0.88)
0.3(0.26-0.34)
0.7(0.65-0.75) |
1.1 (0.9-1.3)
0.4 (0.32-0.48)
0.9(0.78-1.02) |
3.6(3.2-4.0)
1.8(1.6-2.0)
2.7(2.4-3.0) |
4.5%(4.0-5.0) 2.1%(1.9-2.3)
3.2%(2.6-3.8) |
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