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Patient responsiveness to calcitonin salmon nasal spray: a subanalysis of a 2-year study
CLINICAL THERAPEUTICSWOL.
17, NO. 4, 1995
Patient Responsiveness to Calcitonin Salmon Nasal Spray: A Subanalysis of a 2-Year Study Kirsten Overgaurd, ikfD,I Robert Lindsay, MBChB, PhD,2 and Claus Christiunsen, MD’ ‘Center for Clinical & Basic Research, Ballerup, Denmark and 2Helen Hayes Hospital, West Haverstraw, New York
ABSTRACT A subanalysis of results from a randomized, double-blind, placebo-controlled, parallel-group, 2-year study was conducted to evaluate the response of individual patients to therapy with 200 III/d calcitonin salmon nasal spray compared with placebo in postmenopausal women who had low bone mass. All patients received 500 mgld of oral supplemental calcium. A response to therapy was defined as an increase from baseline in lumbar vertebral bone mineral density, measured by use of dual-energy x-ray absorptiometry, at the end of 2 years of treatment. Of 41 valid completers (ie, patients who met the entry criteria, were compliant with the protocol, and completed the study) treated with calcitonin salmon nasal spray, 31 (76%) responded positively to treatment. Of 40 valid completers who received
placebo, 25 (63%) lost bone mass (P = 0.001 between groups). The relative risk of bone loss for patients receiving calcitonin salmon nasal spray was 0.19 (95% confidence interval, 0.07 to 0.50), representing an 81% risk reduction. This subanalysis demonstrates that the benefits of calcitonin salmon nasal spray therapy were seen in the majority of women studied. Calcitonin salmon nasal spray represents an effective therapeutic alternative for osteoporotic women more than 5 years postmenopause who reject or cannot tolerate estrogens or for whom estrogens are contraindicated.
INTRODUCTION Osteoporosis is a global public health problem associated with escalating rates of morbidity and mortality and rising health care costs that are expected to con-
0149.2918/95/$3.50
K. OVERGAARD
ET AL.
tinue to increase with the progressive aging of the world’s population.’ Although osteoporosis afflicts both women and men, the greatest burden of the disease is borne by postmenopausal women.’ Because of its established benefits in preventing bone loss and osteoporotic fractures in postmenopausal women, estrogen replacement is the first-line therapy for this disease.’ However, because of its continued association with cancer of the breast and the endometrium and unwanted side effects such as withdrawal bleeding with concomitant progestogen administration, estrogen therapy is inappropriate or undesirable for many postmenopausal women.2 Therefore, for women who cannot or will not take estrogen, the need exists for therapies that protect against osteoporosis.2 During more than 10 years of worldwide experience, the injectable dosage form of calcitonin salmon has been shown to be an effective alternative for the treatment of postmenopausal osteoporosis.3 Recently, an intranasal dosage form of calcitonin salmon, which should be acceptable to a broader range of patients than the injectable dosage form, has been developed. Clinical studies&l3 have shown that intranasal calcitonin salmon effectively retards bone loss and increases bone mass in postmenopausal women. Calcitonin salmon nasal spray* is an effective therapeutic alternative for osteoporotic women more than 5 years postmenopause who reject or cannot tolerate estrogens or for whom estrogens are contraindicated. The new drug application for this agent, in the United States, included three pivotal trials, which *Trademark: Miacalcin@ (calcitonin-salmon) Nasal Spray (Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey).
studied the 200-IU/d dose.‘2-‘4 In these trials, two of which have been described in published reports, 12*i3the primary efficacy end point was the change from baseline in bone mineral density of the lumbar spine in patients treated with calcitonin salmon nasal spray compared with that of patients who received placebo. Results from these trials showed significant (P 5 0.04) increases in bone mineral density of 2% to 3.6%, compared with patients who received placebo, after 1 to 2 years of therapy with calcitonin salmon nasal spray.14 This report evaluates the outcome of calcitonin salmon nasal spray therapy in a previously reported long-term (Zyear), single-center, parallel-group, double-blind, randomized, placebo-controlled trial12 in terms of the proportion of patients who responded in each treatment group.
PATIENTS AND METHODS Patients were informed in detail of the purpose and nature of the study. The Copenhagen Ethics Committee reviewed and approved the protocol, and the study was performed in accordance with the Declaration of Helsinki. The patient population included healthy white women between the ages of 68 and 72 years who had low bone mass. Patients whose preexisting disease or current therapies could affect calcium metabolism or otherwise confound study results were excluded. Also excluded were patients with evidence of osteomalacia or a history of any of the following: severe cardiopulmonary disorders, including hypertension and serious chronic heart failure; alcohol or drug abuse; diabetes mellitus; or rheumatoid arthritis. The subanalysis discussed in this report includes only patients who received either
681
CLINICAL THERAPEUTICS”
calcitonin salmon nasal spray 200 IU/d or intranasal placebo spray for 2 years. Although other doses of calcitonin salmon nasal spray were studied, the drug is available in the United States only in a 200-IU dose. All patients received 500 mg/d of oral supplemental calcium. The primary efficacy parameter was bone mineral density of the lumbar spine as measured by use of dual-energy x-ray absorptiometry. For this analysis, a responder was defined as a patient with increased lumbar vertebral bone mineral density (a “positive” response) at the end of the study, compared with the baseline value. Results are presented for the 81 valid completers (ie, patients who met the entry criteria, were compliant with the protocol, and completed the study). Data were compared with the use of one-way analysis of variance for quantitative items and Pearson’s chi-square test for qualitative items. The chi-square test was used for statistical comparisons of responders and nonresponders.
Of the patients who received calcitonin salmon nasal spray (200 IU/d plus calcium supplementation), 76% (31 of 41) responded positively to treatment (figure). Of the patients who received placebo plus calcium supplementation, 63% (25 of 40) lost bone mass (figure) (P = 0.001 between groups). The relative risk of 0.19 (95% confidence interval, 0.07 to 0.50) demonstrated an 8 1% reduction in the risk of bone mass loss with calcitonin salmon nasal spray therapy compared with placebo. As reported previously,12 the majority of the adverse events were mild to moderate in severity and transient in nature. Systemic adverse events included headache, dizziness, nausea, and constipation. Local adverse events included nasal secretion and sneezing, nasal dryness, and nasal crusts. No clinically meaningful changes occurred in safety parameters such as blood pressure and blood chemistry. Virtually no difference was noted in the number of adverse events between the calcitonin salmon and the placebo groups.
RESULTS
DISCUSSION
Baseline patient demographics in the calcitonin salmon nasal spray and placebo groups were comparable (table).
As with calcitonins of other origin, calcitonin salmon is a polypeptide that appears to exert its primary therapeutic effect (ie,
AND CONCLUSION
Table. Baseline demographics
of valid completers.*
Characteristic
Calcitonin Salmon Nasal Spray 200 IU/d (n = 41)
(n = 40)
70* 1 21*4 64*9 158 f 7
70 + 1 23 f 5 61 &9 160&6
Age (Y) Time since menopause (y) Body weight (kg) Height (cm)
*Patients who met the entry criteria, were compliant
682
Values are given as mean + SD.
with the protocol,
Placebo
and completed
the study.
K. OVERGAARD ET AL.
-
--
0
.
0 Calcitonin salmon nasal spray 200 W/d (n = 41)
Figure.
l P&&o
(n = 40)
+ Mean
Individual percent changes from baseline in lumbar vertebral bone mineral density in patients treated with calcitonin salmon nasal spray or placebo for 2 years.
inhibition of bone resorption) through a direct physiologic effect on osteoclast activity.i5 The injectable form of this agent has been approved for the treatment of Paget’s disease since 1975 and for hypercalcemia since 1980.3 Injectable calcitonin salmon has been shown to exert positive effects on bone mass in women with postmenopausal osteoporosis during more than a decade of use in this indication.3s’6*‘7 Side effects of this agent have been shown to be mild, transient, and not dose limiting.3 Until recently, the use of calcitonin salmon has been limited by compliance problems associated with the injectable
form.2~3 The recent availability of an intranasal form offers the therapeutic benefits of calcitonin treatment without the drawbacks of parenteral administration.3 Clinical studies4-‘3 have confirmed that calcitonin salmon administered in an intranasal dose form effectively retards bone loss and increases bone mass in postmenopausal women. The objective of this subanalysis was to quantify and characterize the proportion of women who responded positively to therapy with calcitonin salmon nasal spray in a large, double-blind, placebocontrolled, randomized, parallel-group
683
CLINICAL THERAPEUTICS’
clinical trial. The results showed that therapy with calcitonin salmon nasal spray effected a clinical response in the majority of patients studied and reduced the risk of bone mass loss by 81% compared with patients who were administered placebo. The results of this subanalysis confirm the benefits of calcitonin salmon nasal spray therapy in increasing bone mass in women more than 5 years postmenopause with osteoporosis who cannot or will not take estrogen replacement therapy.
porosis by biochemical bone Calcif Tissue ht. 1994;55:8-11.
markers.
200 IU/d
5. Gennari C, Agnusdei D, Camporeale A. Effect of salmon calcitonin nasal spray on bone mass in patients with high turnover osteoporosis. Osteoporosis ht. 1993;50 (Suppl 1):s208-s210.
6. Overgaard K, Hansen MA, Nielsen V-AH, et al. Discontinuous calcitonin treatment of established osteoporosis-effects of withdrawal of treatment. Am J Med. 1990; 89: l-6.
ACKNOWLEDGMENTS This study was supported by a research grant from Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey. The authors thank Donald M. Stablein, PhD, for statistical assistance. Address correspondence to: Claus Christiansen, MD, Center for Clinical & Basic Research, Ballet-up Byvej 222, Ballerup, 2750, Denmark.
REFERENCES Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am .I Med. 1993;94:646-650. Lindsay R. Prevention and treatment of osteoporosis. Lancet. 1993;341:801-805. Wallach S. Calcitonin treatment in osteoporosis. Female Patient. 1992;17:35-50. Munk Nielsen N, von der Recke P, Hansen MA, et al. Estimation of the effect of salmon calcitonin in established osteo-
684
7. Overgaard K. Effect of intranasal salmon calcitonin therapy on bone mass and bone turnover in early postmenopausal women: A dose-response study. Calcif Tissue ht. 1994;55:82-86.
8. Reginster JY, Meurmans L, Deroisy R, et al. A 5-year controlled randomized study of prevention of postmenopausal trabecular bone loss with nasal salmon calcitonin and calcium. Eur J Clin Invest. 1994;24: 565-569.
9. Fioretti P, Gambacciani M, Taponeco F, et al. Effects of continuous and cyclic nasal calcitonin administration in ovariectomized women. Maturitas. 1992;lS: 225-232.
10. Gennari C, Agnusdei D, Montagnani M, et al. An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss. Calcif Tissue Int. 1992;50: 381-383.
11. Reginster JY, Denis D, Deroisy R, et al. Long-term (3 years) prevention of trabecular postmenopausal bone loss with low-
K. OVERGAARD
ET AL.
dose intermittent nasal salmon calcitonin. J Bone Miner Res. 1994;9:69-73.
15. Singer FR, Melvin KEW, Mills BG. Acute effects of calcitonin on osteoclasts in man. Clin Endocrinol.
12. Overgaard Christiansen
K, Hansen
MA, Jensen
SB,
C. Effect of salcatonin given
intranasally on bone mass and fracture rates in established osteoporosis: A doseresponse study. BMJ. 1992;305:556-561. 13. Overgaard
1976;5(Suppl):333s-
340s.
K, Riis BJ, Christiansen
C, et
al. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol. 1989;30:435-442. 14. Data on file, Sandoz Pharmaceuticals
Cor-
poration, East Hanover, New Jersey, 1992.
16. Mazzuoli GF, Passeri M, Gennari C, et al. Effects of salmon calcitonin in postmenopausal osteoporosis: A controlled double-blind clinical study. Calcif Tissue Znt. 1986;38:3-8. 17. Gennari C, Chierichetti 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;38:455-464.
685
17, NO. 4, 1995
Patient Responsiveness to Calcitonin Salmon Nasal Spray: A Subanalysis of a 2-Year Study Kirsten Overgaurd, ikfD,I Robert Lindsay, MBChB, PhD,2 and Claus Christiunsen, MD’ ‘Center for Clinical & Basic Research, Ballerup, Denmark and 2Helen Hayes Hospital, West Haverstraw, New York
ABSTRACT A subanalysis of results from a randomized, double-blind, placebo-controlled, parallel-group, 2-year study was conducted to evaluate the response of individual patients to therapy with 200 III/d calcitonin salmon nasal spray compared with placebo in postmenopausal women who had low bone mass. All patients received 500 mgld of oral supplemental calcium. A response to therapy was defined as an increase from baseline in lumbar vertebral bone mineral density, measured by use of dual-energy x-ray absorptiometry, at the end of 2 years of treatment. Of 41 valid completers (ie, patients who met the entry criteria, were compliant with the protocol, and completed the study) treated with calcitonin salmon nasal spray, 31 (76%) responded positively to treatment. Of 40 valid completers who received
placebo, 25 (63%) lost bone mass (P = 0.001 between groups). The relative risk of bone loss for patients receiving calcitonin salmon nasal spray was 0.19 (95% confidence interval, 0.07 to 0.50), representing an 81% risk reduction. This subanalysis demonstrates that the benefits of calcitonin salmon nasal spray therapy were seen in the majority of women studied. Calcitonin salmon nasal spray represents an effective therapeutic alternative for osteoporotic women more than 5 years postmenopause who reject or cannot tolerate estrogens or for whom estrogens are contraindicated.
INTRODUCTION Osteoporosis is a global public health problem associated with escalating rates of morbidity and mortality and rising health care costs that are expected to con-
0149.2918/95/$3.50
K. OVERGAARD
ET AL.
tinue to increase with the progressive aging of the world’s population.’ Although osteoporosis afflicts both women and men, the greatest burden of the disease is borne by postmenopausal women.’ Because of its established benefits in preventing bone loss and osteoporotic fractures in postmenopausal women, estrogen replacement is the first-line therapy for this disease.’ However, because of its continued association with cancer of the breast and the endometrium and unwanted side effects such as withdrawal bleeding with concomitant progestogen administration, estrogen therapy is inappropriate or undesirable for many postmenopausal women.2 Therefore, for women who cannot or will not take estrogen, the need exists for therapies that protect against osteoporosis.2 During more than 10 years of worldwide experience, the injectable dosage form of calcitonin salmon has been shown to be an effective alternative for the treatment of postmenopausal osteoporosis.3 Recently, an intranasal dosage form of calcitonin salmon, which should be acceptable to a broader range of patients than the injectable dosage form, has been developed. Clinical studies&l3 have shown that intranasal calcitonin salmon effectively retards bone loss and increases bone mass in postmenopausal women. Calcitonin salmon nasal spray* is an effective therapeutic alternative for osteoporotic women more than 5 years postmenopause who reject or cannot tolerate estrogens or for whom estrogens are contraindicated. The new drug application for this agent, in the United States, included three pivotal trials, which *Trademark: Miacalcin@ (calcitonin-salmon) Nasal Spray (Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey).
studied the 200-IU/d dose.‘2-‘4 In these trials, two of which have been described in published reports, 12*i3the primary efficacy end point was the change from baseline in bone mineral density of the lumbar spine in patients treated with calcitonin salmon nasal spray compared with that of patients who received placebo. Results from these trials showed significant (P 5 0.04) increases in bone mineral density of 2% to 3.6%, compared with patients who received placebo, after 1 to 2 years of therapy with calcitonin salmon nasal spray.14 This report evaluates the outcome of calcitonin salmon nasal spray therapy in a previously reported long-term (Zyear), single-center, parallel-group, double-blind, randomized, placebo-controlled trial12 in terms of the proportion of patients who responded in each treatment group.
PATIENTS AND METHODS Patients were informed in detail of the purpose and nature of the study. The Copenhagen Ethics Committee reviewed and approved the protocol, and the study was performed in accordance with the Declaration of Helsinki. The patient population included healthy white women between the ages of 68 and 72 years who had low bone mass. Patients whose preexisting disease or current therapies could affect calcium metabolism or otherwise confound study results were excluded. Also excluded were patients with evidence of osteomalacia or a history of any of the following: severe cardiopulmonary disorders, including hypertension and serious chronic heart failure; alcohol or drug abuse; diabetes mellitus; or rheumatoid arthritis. The subanalysis discussed in this report includes only patients who received either
681
CLINICAL THERAPEUTICS”
calcitonin salmon nasal spray 200 IU/d or intranasal placebo spray for 2 years. Although other doses of calcitonin salmon nasal spray were studied, the drug is available in the United States only in a 200-IU dose. All patients received 500 mg/d of oral supplemental calcium. The primary efficacy parameter was bone mineral density of the lumbar spine as measured by use of dual-energy x-ray absorptiometry. For this analysis, a responder was defined as a patient with increased lumbar vertebral bone mineral density (a “positive” response) at the end of the study, compared with the baseline value. Results are presented for the 81 valid completers (ie, patients who met the entry criteria, were compliant with the protocol, and completed the study). Data were compared with the use of one-way analysis of variance for quantitative items and Pearson’s chi-square test for qualitative items. The chi-square test was used for statistical comparisons of responders and nonresponders.
Of the patients who received calcitonin salmon nasal spray (200 IU/d plus calcium supplementation), 76% (31 of 41) responded positively to treatment (figure). Of the patients who received placebo plus calcium supplementation, 63% (25 of 40) lost bone mass (figure) (P = 0.001 between groups). The relative risk of 0.19 (95% confidence interval, 0.07 to 0.50) demonstrated an 8 1% reduction in the risk of bone mass loss with calcitonin salmon nasal spray therapy compared with placebo. As reported previously,12 the majority of the adverse events were mild to moderate in severity and transient in nature. Systemic adverse events included headache, dizziness, nausea, and constipation. Local adverse events included nasal secretion and sneezing, nasal dryness, and nasal crusts. No clinically meaningful changes occurred in safety parameters such as blood pressure and blood chemistry. Virtually no difference was noted in the number of adverse events between the calcitonin salmon and the placebo groups.
RESULTS
DISCUSSION
Baseline patient demographics in the calcitonin salmon nasal spray and placebo groups were comparable (table).
As with calcitonins of other origin, calcitonin salmon is a polypeptide that appears to exert its primary therapeutic effect (ie,
AND CONCLUSION
Table. Baseline demographics
of valid completers.*
Characteristic
Calcitonin Salmon Nasal Spray 200 IU/d (n = 41)
(n = 40)
70* 1 21*4 64*9 158 f 7
70 + 1 23 f 5 61 &9 160&6
Age (Y) Time since menopause (y) Body weight (kg) Height (cm)
*Patients who met the entry criteria, were compliant
682
Values are given as mean + SD.
with the protocol,
Placebo
and completed
the study.
K. OVERGAARD ET AL.
-
--
0
.
0 Calcitonin salmon nasal spray 200 W/d (n = 41)
Figure.
l P&&o
(n = 40)
+ Mean
Individual percent changes from baseline in lumbar vertebral bone mineral density in patients treated with calcitonin salmon nasal spray or placebo for 2 years.
inhibition of bone resorption) through a direct physiologic effect on osteoclast activity.i5 The injectable form of this agent has been approved for the treatment of Paget’s disease since 1975 and for hypercalcemia since 1980.3 Injectable calcitonin salmon has been shown to exert positive effects on bone mass in women with postmenopausal osteoporosis during more than a decade of use in this indication.3s’6*‘7 Side effects of this agent have been shown to be mild, transient, and not dose limiting.3 Until recently, the use of calcitonin salmon has been limited by compliance problems associated with the injectable
form.2~3 The recent availability of an intranasal form offers the therapeutic benefits of calcitonin treatment without the drawbacks of parenteral administration.3 Clinical studies4-‘3 have confirmed that calcitonin salmon administered in an intranasal dose form effectively retards bone loss and increases bone mass in postmenopausal women. The objective of this subanalysis was to quantify and characterize the proportion of women who responded positively to therapy with calcitonin salmon nasal spray in a large, double-blind, placebocontrolled, randomized, parallel-group
683
CLINICAL THERAPEUTICS’
clinical trial. The results showed that therapy with calcitonin salmon nasal spray effected a clinical response in the majority of patients studied and reduced the risk of bone mass loss by 81% compared with patients who were administered placebo. The results of this subanalysis confirm the benefits of calcitonin salmon nasal spray therapy in increasing bone mass in women more than 5 years postmenopause with osteoporosis who cannot or will not take estrogen replacement therapy.
porosis by biochemical bone Calcif Tissue ht. 1994;55:8-11.
markers.
200 IU/d
5. Gennari C, Agnusdei D, Camporeale A. Effect of salmon calcitonin nasal spray on bone mass in patients with high turnover osteoporosis. Osteoporosis ht. 1993;50 (Suppl 1):s208-s210.
6. Overgaard K, Hansen MA, Nielsen V-AH, et al. Discontinuous calcitonin treatment of established osteoporosis-effects of withdrawal of treatment. Am J Med. 1990; 89: l-6.
ACKNOWLEDGMENTS This study was supported by a research grant from Sandoz Pharmaceuticals Corporation, East Hanover, New Jersey. The authors thank Donald M. Stablein, PhD, for statistical assistance. Address correspondence to: Claus Christiansen, MD, Center for Clinical & Basic Research, Ballet-up Byvej 222, Ballerup, 2750, Denmark.
REFERENCES Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am .I Med. 1993;94:646-650. Lindsay R. Prevention and treatment of osteoporosis. Lancet. 1993;341:801-805. Wallach S. Calcitonin treatment in osteoporosis. Female Patient. 1992;17:35-50. Munk Nielsen N, von der Recke P, Hansen MA, et al. Estimation of the effect of salmon calcitonin in established osteo-
684
7. Overgaard K. Effect of intranasal salmon calcitonin therapy on bone mass and bone turnover in early postmenopausal women: A dose-response study. Calcif Tissue ht. 1994;55:82-86.
8. Reginster JY, Meurmans L, Deroisy R, et al. A 5-year controlled randomized study of prevention of postmenopausal trabecular bone loss with nasal salmon calcitonin and calcium. Eur J Clin Invest. 1994;24: 565-569.
9. Fioretti P, Gambacciani M, Taponeco F, et al. Effects of continuous and cyclic nasal calcitonin administration in ovariectomized women. Maturitas. 1992;lS: 225-232.
10. Gennari C, Agnusdei D, Montagnani M, et al. An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss. Calcif Tissue Int. 1992;50: 381-383.
11. Reginster JY, Denis D, Deroisy R, et al. Long-term (3 years) prevention of trabecular postmenopausal bone loss with low-
K. OVERGAARD
ET AL.
dose intermittent nasal salmon calcitonin. J Bone Miner Res. 1994;9:69-73.
15. Singer FR, Melvin KEW, Mills BG. Acute effects of calcitonin on osteoclasts in man. Clin Endocrinol.
12. Overgaard Christiansen
K, Hansen
MA, Jensen
SB,
C. Effect of salcatonin given
intranasally on bone mass and fracture rates in established osteoporosis: A doseresponse study. BMJ. 1992;305:556-561. 13. Overgaard
1976;5(Suppl):333s-
340s.
K, Riis BJ, Christiansen
C, et
al. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol. 1989;30:435-442. 14. Data on file, Sandoz Pharmaceuticals
Cor-
poration, East Hanover, New Jersey, 1992.
16. Mazzuoli GF, Passeri M, Gennari C, et al. Effects of salmon calcitonin in postmenopausal osteoporosis: A controlled double-blind clinical study. Calcif Tissue Znt. 1986;38:3-8. 17. Gennari C, Chierichetti 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;38:455-464.
685