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ORIGINAL ARTICLE

Comparison of Intranasal Calcitonin and Intravenous Ibandronic acid for the treatment of Osteoporosis in Postmenopausal Women

Ashish Madanlal Narang

GMC, Mumbai.
Address for Correspondence:

Ashish Madanlal Narang
GMC, Mumbai.

 

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 1Go). 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)

Reference :

  1. Santoro NF, Col NF, Eckman MH, et al. 1999 Therapeutic controversy:
    hormone replacement therapy—where are we going? J Clin Endocrinol Metab.
     84:1798–1812. URL:http://jcem.endojournals.org/cgi/content/full/84/6/1798?ijkey
    =ead655586a268538c6b8b7b48db799edd8f14be3&keytype2=tf_ipsecsha

  2. Stakkestad JA ,Benevolenskaya LI, Stepan JJ et al.2003 Intravenous ibandronate injections given every three months: a new treatment option to prevent bone loss in postmenopausal women .Annals of the rheumatic diseases  2003, 62 :10, pp. 969-975 

  3. Overgaard K, Riis BJ, Christiansen C, Podenphant J, Johansen JS. 1989 Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol. 30:435–442.  URL:http://www.ncbi.nlm.nih.gov/pubmed/2688995?dopt=Abstract

  4. Overgaard K, Hansen MA, Jensen SB, Christiansen C. 1992 Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis: a dose-response study. Br Med J. 305:556–561.

  5. Ellerington MC, Hillard TC, Whitcroft SIJ, et al. 1996 Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis. Calcif Tissue Int. 59:6–11. URL :http://www.ncbi.nlm.nih.gov/pubmed/8661976?dopt=Abstract

 

This is a peer reviewed paper 

Please cite as: Ashish Madanlal Narang: Comparison of Intranasal Calcitonin and Intravenous Ibandronic acid for the treatment of Osteoporosis in Postmenopausal Women

J.Orthopaedics 2010;7(2)e9

URL: http://www.jortho.org/2010/7/2/e9

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