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From the Clinical Research Centers |
Medical College of Virginia (R.W.D.), Richmond, Virginia 23219; Medical University of South Carolina (N.H.B.), Charleston, South Carolina 29401; Clinical Research Center of South Florida (M.P.E.), Stuart, Florida 34996; Brigham and Women’s Hospital (B.W.W.), Boston, Massachusetts 02115; University of Chicago (M.J.F.), Chicago, Illinois 60637; and Merck and Co., Inc. (B.M., L.W., M.E.S., G.J.G., M.E.M.), West Point, Pennsylvania 19486
Address correspondence and requests for reprints to: Mary E. Melton, M.D., Merck and Co., Inc., WS2C-55, One Merck Drive, Whitehouse Station, New Jersey 08889.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Both intranasal calcitonin and alendronate have been reported to be associated with increases in BMD and decreases in bone turnover (2, 3, 4, 5, 6, 7). Although the increases in BMD reported with alendronate, in general, are greater than those reported with calcitonin, a direct comparison is necessary to adequately understand the relative efficacy of these two therapies. Although one study has been reported comparing alendronate at doses of 10 and 20 mg daily with intranasal calcitonin at a dose of 100 IU daily (8), no comparison studies have been reported with the doses of alendronate (10 mg) and intranasal calcitonin (200 IU) commonly used for treating osteoporosis. This study was, therefore, designed to compare directly the effects of intranasal calcitonin and alendronate on BMD and bone turnover when used for treatment of osteoporosis in postmenopausal women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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This prospective, randomized study was conducted at 24 centers across the United States. The centers recruited ambulatory women at least 5 yr postmenopause with osteoporosis. Patients were required to have a BMD by dual-energy x-ray absorptiometry (DXA) at least 2 SD below the mean for a reference population of young women [based on the reference database provided by Hologic, Inc. (Waltham, MA)] at either the PA lumbar spine or femoral neck and, in addition, a BMD measurement at least 1 SD below the young normal mean at the other site. These criteria identify women who would be among the appropriate candidates for therapeutic intervention according to the National Osteoporosis Foundation guidelines (9). Patients with a BMD more than 4 SD below the young normal mean at either the PA lumbar spine or femoral neck, a prevalent vertebral fracture on lateral thoracic or lumbar spine radiographs, or a history of minimal trauma hip fracture were excluded due to the use of a placebo in this study. Patients were also 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. A history of a gastrointestinal disorder (other than an esophageal motility disorder) or use of a nonsteroidal anti-inflammatory agent was not a reason for exclusion.
Ethics committee approval was obtained for all study sites. Informed consent was obtained from all patients before performance of any study procedures. A total of 977 women were evaluated for inclusion, of which 941 underwent BMD testing. Two hundred ninety-nine women who met all of the eligibility criteria following medical history, physical examination, and laboratory assessment were randomized. The primary reason screened patients did not proceed to randomization was that they did not meet BMD entry criteria.
Treatment
Patients were randomly assigned to one of the following groups: oral alendronate sodium (Fosamax; Merck & Co., Inc., West Point, PA), 10 mg daily; matching alendronate placebo daily; or open-label intranasal calcitonin-salmon (Miacalcin Nasal Spray; Novartis, East Hanover, NJ), 200 IU daily. Alendronate and matching placebo were manufactured and supplied by Merck & Co., Inc. Intranasal calcitonin was purchased from a pharmaceutical wholesale company. Calcitonin was distributed to patients in the original packaging. Half as many patients were randomized to the placebo group as were randomized to the alendronate and calcitonin groups (2:2:1, alendronate:calcitonin:placebo). Alendronate and matching alendronate placebo were blinded; therefore, neither the patient nor study personnel knew whether the patients receiving a tablet were receiving active drug or placebo. Patient assignment to treatment group was determined with a randomized allocation schedule. Administration and storage of the drugs were performed in accordance with the recommendations supplied by each drug’s manufacturer. Patients assigned to either alendronate or alendronate placebo were instructed to take the tablet orally in the morning, at least 30 min before the first meal of the day with 6–8 ounces of plain water, and to remain upright for at least 30 min after dosing and until after the first food of the day. Patients assigned to calcitonin were instructed to administer one 200-IU dose (one spray) intranasally each day, alternating nostrils daily. The patients also received instructions for activating the calcitonin pump (10). Both study sites and patients were instructed to store unopened bottles of calcitonin in a refrigerator. The patients receiving calcitonin were instructed to switch to a new bottle every 2 weeks. Compliance with therapy was determined by patient reporting of the days on and off therapy.
Dietary calcium intake was assessed with a questionnaire (11). Patients whose daily dietary calcium intake was less than 1000 mg were given supplemental calcium carbonate (OsCal 500; SmithKline Beecham Consumer Healthcare, Pittsburgh, PA) to achieve a total daily calcium intake of at least 1000 mg. A vitamin D supplement containing 400 IU was provided daily throughout the study to all participants.
Data collection and review procedures were performed blinded to treatment group. Follow-up bone densitometry was not made available to patients or study personnel (with the exception of the DXA operator).
Efficacy and safety measurements
BMD measurements were performed with DXA at baseline, 6 months, and 12 months following randomization. Measurements of BMD were analyzed in a blinded fashion by a central quality assurance center (BonaFide, Madison, WI). The primary efficacy end point was lumbar spine BMD measured in the PA projection. Femoral neck and hip trochanter BMD were secondary efficacy end points.
All serum and urine specimens were collected in the morning after an overnight fast and were analyzed by a central laboratory (MAYO Medical Laboratories, Rochester, MN). Biochemical markers of bone turnover were collected at randomization, 6 months, and 12 months. Serum bone-specific alkaline phosphatase (BSAP) was measured as a marker of bone formation with the Tandem-R Ostase kit (Hybritech, Inc., San Diego, CA). Urinary N-telopeptide of type I collagen adjusted for urinary creatinine (NTx) was measured as a marker of bone resorption with the Osteomark enzyme-linked immunoassay (Ostex International, Inc., Seattle, WA).
Routine laboratory parameters for safety (chemistry, hematology, and urinalysis) were collected at screening, 6 months, and 12 months. Clinical adverse experiences (AEs) were assessed at each study visit. The investigator was asked to assess relationship to study drug for all AEs. Those described as possibly, probably, or definitely related to study drug were included in the assessment of drug-related AEs. Serious AEs included those requiring hospitalization and those that were life-threatening or fatal. Information on clinical fractures was collected through AE reporting.
Statistical analysis
Statistical analyses were performed with the SAS version 6.12 statistical package (SAS Institute, Inc., Cary, NC). Baseline demographics and clinical characteristics were compared between treatment groups with t tests (continuous data) and Fisher’s exact tests (categorical data).
ANOVA was used to make comparisons between treatment groups for BMD end points. This model included terms for treatment and site. Tests comparing the treatment groups were declared significant at the 0.05 level. Because the study had one primary end point, no adjustment for multiple comparisons was made. An ANOVA was also used to compare treatments with respect to the biochemical markers of bone turnover. Because the biochemical marker data were distributed in a log-normal fashion, the analysis was performed on the log-transformed data. Results were back-transformed and reported as percent change from baseline. 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 end points and biochemical markers of bone turnover. That is, all patients who had at least one dose of therapy, a baseline measurement, and at least one postrandomization observation were included in the analysis. In this analysis, in the event of missing data, the last postrandomization observation was carried forward to subsequent time points. A per protocol analysis was also performed for the biochemical markers of bone turnover.
Incidences of AEs were compared between treatment groups with Fisher’s exact tests. Analyses were conducted on all reported AEs. The percentages of patients with upper gastrointestinal AEs and fracture AEs were also analyzed. All patients treated were included in the analysis of safety data.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The characteristics of each treatment group were similar at
baseline (Table 1
). The women ranged in
age from 45–84 yr, with a mean age of 64 yr. Most of the women were
Caucasian (97%). The mean BMD at the lumbar spine and femoral neck at
baseline corresponded to T-scores of -2.5 and -2.7, respectively. The
percentage of patients with selected risk factors for osteoporosis was
also similar between treatment groups. Eleven percent of the patients
had a history of bilateral oophorectomy, 47% reported current or prior
tobacco use, 24% reported caffeine intake of more than three cups per
day, 37% reported a family history of osteoporosis, and 55% reported
a history of fracture. The most common medical diagnoses reported at
baseline included hypercholesterolemia (37%), drug allergy (35%),
hysterectomy (27%), and osteoarthritis (24%). The mean compliance
with study medication was 85% with alendronate, 92% with calcitonin,
and 92% with placebo.
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Significantly greater increases in BMD were seen in the group
treated with alendronate compared with the group treated with
calcitonin at the lumbar spine (P < 0.001) and
trochanter (P < 0.001) at 6 months and at the lumbar
spine (P < 0.001), femoral neck (P <
0.001), and trochanter (P < 0.001) at 12 months (Fig. 1). Significantly greater increases in
BMD were seen with alendronate as compared with placebo at 6 and 12
months at the lumbar spine (P < 0.001), femoral neck
(P < 0.001), and trochanter (P < 0.01
at 6 months, P < 0.001 at 12 months). At the femoral
neck, significantly greater increases in BMD were seen with calcitonin
as compared with placebo at 6 and 12 months (P <
0.01). The increases in BMD at the lumbar spine and trochanter were not
significantly different between the calcitonin and placebo groups at
either 6 or 12 months.
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Biochemical markers of bone turnover
Substantially greater decreases in both serum BSAP and urinary NTx
(Fig. 2) were seen in the alendronate
group as compared with the calcitonin and placebo groups at all time
points measured (P < 0.001). At 12 months, serum BSAP
had declined by 43% in the alendronate group, 9% in the calcitonin
group, and 2% in the placebo group. Urinary NTx had decreased by 62%
with alendronate and 11% with calcitonin, and had increased by 2%
with placebo. No significant differences in serum BSAP at 12 months or
in urinary NTx at 6 or 12 months were demonstrated between the group
treated with calcitonin and the placebo group. The decrease in serum
BSAP in the calcitonin group was significantly different from placebo
at 6 months (P < 0.05).
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The per protocol analysis of the serum BSAP and urinary NTx results were similar, except for the lack of statistical difference between the calcitonin and placebo BSAP results at 6 months, and a significant decrease from baseline in serum BSAP with calcitonin at month 6 (P < 0.001) but not at month 12.
Tolerability
The percentage of patients reporting any clinical AE was similar
in each group (Table 2). Serious AEs were
also reported in a similar percentage of patients in each group, as
were drug-related AEs. There were no significant differences between
groups in percentage of patients reporting any AE, any serious AE, or
drug-related AE. The percentage of patients who withdrew due to an AE
was also similar in each group as was the percentage who withdrew due
to a drug-related AE.
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), statistical differences were found
between the alendronate and calcitonin groups for the following
specific AE categories: nasal irritation, epistaxis, and dyspepsia. A
statistical difference between the calcitonin and placebo groups was
found for the category of acid regurgitation. No differences in the
percentage of patients reporting any drug-related AEs were found
between the alendronate and alendronate placebo groups. The percentage of patients reporting an upper gastrointestinal AE was 26% in the alendronate group, 13% in the calcitonin group, and 22% in the alendronate placebo group (P < 0.05 alendronate vs. calcitonin). Drug-related upper gastrointestinal AEs were reported in 17% of the alendronate group, 1% of the calcitonin group, and 17% of the alendronate placebo group (P < 0.001 alendronate vs. calcitonin, P < 0.001 calcitonin vs. alendronate placebo). No differences in the percentage of patients reporting upper gastrointestinal AEs were found between the alendronate and the alendronate placebo groups. The percentage of patients reporting a fracture was small and not different between groups [alendronate (5%), calcitonin (5%), and placebo (0%)].
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The changes in BMD and biomarkers observed in this trial are consistent with the published data for the treatment effect of each drug. Previous studies with alendronate have shown 1-yr increases in BMD at the spine and hip of a magnitude similar to those seen in this trial (2, 3). Intranasal calcitonin at a dose of 200 IU daily was reported to increase BMD from baseline at 1 yr by approximately 1–3% at the lumbar spine, 0% at the femoral neck, and 2.5% at the hip trochanter in women at least 5 yr postmenopause (6, 7). Although no statistical difference in BMD effect was seen between calcitonin and placebo at the spine or trochanter in this study, other studies have shown a statistical difference between calcitonin and placebo (10). However, the absolute magnitudes of the changes in BMD demonstrated with calcitonin in this study are similar to the changes seen in other studies. In a large 5-yr randomized placebo-controlled trial of 1175 postmenopausal women with low bone mass and a prevalent vertebral fracture, the percent change from baseline after 3 yr with 200 IU intranasal calcitonin was approximately 1.3% at the spine and was not different from placebo (12). Because all groups, including placebo, received vitamin D and at least 1500 mg calcium daily, the lack of effect between calcitonin and placebo may, in part, be due to an effect of calcium and vitamin D to preserve BMD. 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 (10), and bottles were changed every 2 weeks. 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 quality assurance center to ensure reliability of the BMD data.
There are several strengths of this study. First, women who participated in the study were at least 5 yr postmenopause and had low BMD (T-score <-2.0) but did not have a prevalent vertebral fracture or history of hip fracture. Exclusion criteria were used to ensure that women who were screened and found to be at greatest risk of fracture (T-score <-4.0 and/or previous fractures) would not enter the trial but instead be considered for active therapy. Women who were less than 5 yr postmenopause were not included consistent with the prescribing information for intranasal calcitonin (10). 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) and are included among those for whom the recently released National Osteoporosis Foundation guidelines recommend treatment (9).
Tolerability was assessed in this trial by examining the percentage of patients reporting any AE. The percentage of patients reporting any AE was similar for all treatment groups (including placebo), indicating that both alendronate and intranasal calcitonin are generally well tolerated. However, more women receiving a tablet (i.e. blinded alendronate or placebo) reported drug-related digestive AEs (acid regurgitation and dyspepsia) than women on intranasal calcitonin. As seen in larger randomized placebo-controlled trials (2, 3, 4), there was no statistical difference between AEs for women on alendronate and those on placebo. It seems that gastrointestinal AEs are more likely to be reported in those women who received a tablet. Respiratory events (nasal irritation and epistaxis) were seen more commonly in the group receiving intranasal calcitonin. There was no matching intranasal calcitonin placebo, however, making interpretation of these events difficult. Yet these results are consistent with clinical practice and prior reports of side effects noted with intranasal calcitonin and alendronate. A similar percentage of patients withdrew due to a drug-related AE in each treatment group, which indicates that the overall tolerability of these therapies is similar.
There are several limitations to this study. This study was designed to examine BMD, rather than fracture, as a primary end point, and the study was not large enough to ascertain fracture efficacy. Fracture information was collected as part of AE reporting, so only those fractures that came to clinical attention were reported. No follow-up vertebral radiographs were performed, so there is no information available on asymptomatic vertebral fractures or vertebral morphometry. To determine reduction in fracture risk for this cohort would have required a much larger sample size, especially since women enrolled in this study were required to have no evidence of prevalent vertebral fractures, a major risk factor for future vertebral compression fractures. Hence, conclusions about relative fracture risk reduction between these two drugs cannot be drawn from these data. However, there is evidence that greater increases in BMD are associated with greater reductions in fracture events in those receiving alendronate (13). No similar data exist for calcitonin. Also, the results reported here are for 12 months of therapy. To evaluate a longer duration of therapy, the study is being extended to assess the effects of alendronate and calcitonin over 24 months. In addition, the trial was conducted as a double-blind study for alendronate and placebo, but, because an intranasal calcitonin placebo was not available, the calcitonin was administered as open-label drug. It is unlikely that administration of open-label drug would alter the BMD or biochemical marker results, and, moreover, the magnitude of the differences in BMD between alendronate and intranasal calcitonin is quite large. However, the open-label administration of intranasal calcitonin would certainly affect the reporting of AEs. The results reported here were obtained in postmenopausal women with osteoporosis and cannot be generalized to other populations such as men, those with glucocorticoid-associated osteoporosis, or for the prevention of osteoporosis. Also, it is conceivable that other markers of turnover (e.g. C-telopeptide, deoxypyridinoline, or procollagen peptide) could be affected more by calcitonin than were urinary NTx or serum BSAP, the markers that were evaluated in this study (5, 6, 14). Finally, confirmation of these results in a separate study is needed. Results at 12 months of a second similarly designed study have been analyzed, and both the BMD and biochemical marker results are similar to the results seen in the study reported here (15, 16).
In conclusion, this randomized trial comparing intranasal calcitonin and alendronate in postmenopausal women with osteoporosis demonstrated that women treated with alendronate achieved significantly greater increases in BMD than did those treated with calcitonin at the lumbar spine and hip trochanter at 6 and 12 months and at the femoral neck at 12 months. Moreover, alendronate was more effective in suppressing bone turnover than calcitonin. Intranasal calcitonin was found to increase femoral neck BMD as compared with placebo; however, the effect of intranasal calcitonin on lumbar spine and trochanter BMD and biochemical markers of bone turnover at 12 months was no different from placebo.
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Acknowledgments |
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Clinical sites and primary investigators: David J. Baylink, M.D. (Jerry Pettis VAMC, Loma Linda, CA); Norman H. Bell, M.D. (Medical University of South Carolina, Charleston, SC); Sheldon Berger, M.D. (Chicago Center for Clinical Research, Chicago, IL); Kathleen Colleran, M.D. (University of New Mexico, Albuquerque, NM); Christine Cook, M.D. (University of Louisville, Louisville, KY); Robert W. Downs, Jr., M.D. (Medical College of Virginia, Richmond, VA); Michael S. Doyle, M.D. (William Beaumont Hospital, Birmingham, MI); Mark P. Ettinger, M.D., F.A.C.R. (Clinical Research Center of South Florida, Stuart, FL); Murray Favus, M.D. (University of Chicago, Chicago, IL); Barbara Feuerstein, M.D. (SUNY Health Science Center, Syracuse, NY); James I. Fidelholtz, M.D. (Hightop Medical Research Center, Cincinnati, OH); F. Michael Gloth, M.D. (Union Memorial Hospital, Baltimore, MD); Robert Jacobson, M.D.; Norman S. Koval, M.D. (Center for Rheumatology & Bone Research, Wheaton, MD); Robin Kroll, M.D. (North Seattle Women’s Group, Seattle, WA); Daniel Laury, M.D. (Medford, OR); Robert Levin, M.D. (Clinical Research of West Florida, Inc., Clearwater, FL); Charles P. Lucas, M.D. (William Beaumont Hospital, Birmingham, MI); Veronica Piziak, M.D., Ph.D. (Scott & White Clinic, Temple, TX); Terry Poling, M.D. (Family Medicine East, Wichita, KS); John Robbins, M.D. (UCDMC General Medicine Research Group, Sacramento, CA); Louis L. Shane, M.D. (Endocrinology Associates of Westchester, P.C., White Plains, NY); Thomas E. Snyder, M.D. (Bowman Gray School of Medicine, Winston-Salem, NC); Randall R. Stoltz, M.D. (GFI Pharmaceutical Services, Inc., Evansville, IN); Thomas Stovall, M.D. (Bowman Gray School of Medicine, Winston-Salem, NC); Richard P. Tonino, M.D. (Fletcher Allen Health Care, Burlington, VT); Sylvia Vela, M.D. (University of New Mexico, Albuquerque, NM); Brian Walsh, M.D. (Brigham & Women’s Hospital, Boston, MA).
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Footnotes |
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Received October 5, 1999.
Revised December 17, 1999.
Revised January 21, 2000.
Accepted January 26, 2000.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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), 200 IU intranasal calcitonin (CT, 
), and
placebo tablet (PBO, 
) over 12 months. P values for
between group comparisons are presented.