Original Paper Gynecol Obstet Invest 1992;33:168—171
Clinic of Obstetrics and Gynecology, University of Rome ‘La Sapienza’, Policlinico Umberto I, Rome, Italy
Keywords Intranasal calcitonin Bone density Menopause Osteoporosis
Intranasal Salmon Calcitonin in Postmenopausal Osteoporosis: Effect of Different Therapeutic Regimens on Vertebral and Peripheral Bone Density
Abstract Sixty postmenopausal women were randomly assigned to three types of treat ment with intranasal salmon calcitonin (SCT) plus calcium 500 mg daily (group A: 100IU daily of SCT; group B: 100 IU daily of SCT for alternate cycles of 2 months with a 1-month interval; group C: 100 IU daily of SCT for alternate cycles of 3 months of treatment followed by a 3-month interval) or calcium 500 mg daily alone (control group). Lumbar density significantly decreased in the control group while it maintained the initial value in both continuously or cyclically treated groups. The bone density of the proximal and distal forearm in treated and control groups did not show significant changes after 12 months.
Introduction Several clinical studies have documented the efficacy of calcitonin in the treatment of postmenopausal osteo porosis; results generally show either a suppression of bone loss [1, 2] or an increment in bone mass [3-6]. The treatment with calcitonin also has a place in the pre vention of postmenopausal osteoporosis in women in whom estrogens are not indicated. Calcitonin administra tion, whether injective or intranasal, proved to be effi cient in the reduction in bone loss in healthy postmeno pausal women when compared to nontreated controls [79], Moreover, the improvement in both acceptability and compliance obtained with intranasal calcitonin enables its long-term use [9, 10]. Some controversies concerning
Received: August 26. 1991 Accepted: September 19.1991
the minimum effective dose for the prevention and the efficacy of the different forms of treatment (cyclic or continuative) are still being debated. The aim of our prospective 1-year randomized con trolled study is to verify the effect of different therapeutic regimens of intranasal salmon calcitonin (SCT) on verte bral and radial bone density in healthy postmenopausal women.
Materials and Methods Sixty postmenopausal women were included in the study. All had referred themselves to the menopausal clinic for an occasional check up. The patients were all between 52 and 60 years of age and had been in natural menopause for 2-5 years. None had received hor-
G. Perrone Clinic of Obstetrics and Gynecology University o f Rome ‘La Sapienza' Policlinico Umberto 1.1— 00199 Rome (Italy)
© 1992 S. Kargcr AG. Basel 0378-7346/92/0333-0168 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
G. Perrone P. Galoppi M. Valente O. Capri C. D ’Ubaldo G. Anelli L. Zichella
Age, years
Group A
Group B
Group C
Controls
55±3
54 + 2
55 + 4
56 ± 3
4± 1
4±2
3± 1
Years after menopause
3± 1
Height, cm
161 ± 7
159 ± 6
160 ± 7
161 ± 5
Weight, kg
65±4
63 ± 5
64 ± 3
65 ± 5
Proximal forearm BMD, g/cm 2
0.584 ±0.78
0.583 ±0.38
0.553±0.39
0.589 ±0.43
Distal forearm, BMD, g/cm 2
0.467 ±0.38
0.438 ±0.65
0.427 ±0.57
0.470 ±0.61
L 2-L 4 BMD. g/cm 2
0.779 ±0.85
0.732 ±0.78
0.748 ±0.71
0.775 ±0.56
monal treatment nor taken any drug active on bone metabolism for at least 1 year before the study. Three types of treatment were ran domly assigned: group A: 100IU daily of intranasal SCT for 1 year plus calcium 500 mg daily (n = 15); group B: 100 IU daily of intra nasal SCT for alternate cycles of 2 months with a 1-month interval plus calcium 500 mg daily (n= 15), and group C: 100 IU daily of SCT spray for alternate cycles of 3 months of treatment followed by a 3-month interval plus calcium 500 mg daily (n = 15). A control group (n = 15), homogeneous in age and in menopausal stage, received calcium alone. The study period was 1 year. The bone mineral density o f the forearm was measured every 6 months by single photon absorptiom etry with a source of iodine-125 (Norland 2780) in the proximal and distal sites. The trabecular bone contents of these regions are approx imately 13 and 55%, respectively [11]. The bone density of the lum bar spine (L2-L4) was measured every 6 months by dual photon Xray absorptiometry (Hologic QDR-X 1000). In our department, the long-term precision of the two techniques in vivo is 3 and 1%, respec tively. Bone mineral density was measured before treatment and every 6 months. The difference in the densities was expressed as a percentage of basal values. The averages were compared using Student’s t test for paired and unpaired data. The differences between groups were tested by one-way analysis of variance.
Results All patients in group A completed the treatment. Group B had 1 dropout (n = 14) due to climacteric symp toms that required treatment with estrogen. Group C had 3 dropouts (n = 12), 1 due to a poor compliance and 2 due to personal reasons. All subjects of the control group completed the study. The patients’ clinical data and the averages and standard deviations of the densities measured before treatment are indicated in table 1.
The densities at the radial and vertebral sites are homogeneous. Figures 1-3 show the mean changes in radial and spi nal bone mineral densities in the treated and control groups. No significant difference was found within each single group in radial and vertebral bone sites after 6 and 12 months. The vertebral bone mineral density of the con trol group decreased significantly after 12 months, while that of the treated women was constant. No significant difference was found between cyclical and continuous treatment.
Discussion Calcitonin administered intranasally for 1 year, con tinuously or cyclically, was well tolerated by the post menopausal women; no adverse reactions were reported and only few patients abandoned the treatment before the end of the study. Bone mineral density measured at the lumbar spine significantly decreased in the control group while it main tained the initial value in all treated groups. Therefore, calcitonin given intranasally, according to different thera peutic regimens, showed a maintenance effect on the ver tebral bone density. At the radius, both treated women and controls did not show significant changes after 12 months of observation. The well-known effect of the injective SCT in the pre vention of bone loss [8] has also been demonstrated by the intranasal SCT [7, 9], Only one study [7] showed that 100 IU per day of intranasal calcitonin administered for 2 years had different effects on the spine as compared to the radius in healthy postmenopausal women.
169
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T a b le 1. Clinical data, lumbar and peripheral bone mineral density (BMD) of the treated postmenopausal women
(%> Proximal forearm bm d
Fig. 1. Mean (SD) changes in bone min eral density in distal forearm in postmeno pausal women treated with different regi mens of intranasal SCT. * = Group A: • = group B; o = group C; A = controls.
bm d
(%)
bm d
(%)
Fig. 2. Mean (SD) changes in bone min eral density in distal forearm in postmeno pausal women treated with different regi mens of intranasal SCT. * = Group A; • = group B; o = group C; A = controls.
L 2 - L4
170
Perrone/Galoppi/Valente/Capri/D'Ubaldo/ Anelli/Zichella
Effect of Different Regimens of Intranasal Calcitonin on Bone Density
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
Fig. 3. Mean (SD) changes in bone min eral density in L2-L4 in postmenopausal women treated with different regimens of intranasal SCT. * = Group A; • = group B; o = group C; A = controls.
Although our study refers to only 1 year of treatment, we can confirm a significant protective effect with respect to vertebral bone loss after 12 months, while showing no effect on the radius. The decrease in vertebral bone den sity is more precocious and rapid with comparison to the measurable changes in the other skeletal sites [12]: in fact, the changes of bone density after 12 months measured at the distal and proximal radius in both control and treated groups arc not significant. Since the vertebral fracture is one of the most impor tant consequences of postmenopausal osteoporosis, pre venting bone loss in the spine is a crucial aim. Although estrogen is the most efficient prevention, calcitonin has
proven to be a valid alternative. We have confirmed that 100 IU per day of intranasal SCT can prevent vertebral bone loss. Cyclical administration of calcitonin has proven to be an effective treatment for postmenopausal osteoporosis [10, 13]; according to our results, 100 IU of spray SCT administered for alternative cycles has effects similar to those obtained with the continuous administration in the prevention of bone loss. Such a result can be of relevance in considering the improvement of the compliance and the cost advantage that cyclical administration may have.
References 5 Mazzuoli, G.F.; Passeri, M.; Gennari, C.; Mini sole, S.; Antonelli, R.; Valtorta, C.; Palummeri, E.; Cervellin, G.F.; Gonelli, S.: Francini, G.: Effects of salmon calcitonin in postmenopausal osteoporosis: a controlled double-blind clinical study. Calif. Tissue Int. 38:3-8 (1986). 6 Gruber, H.E.; Ivey, J.L.; Baylink, D.J.; Mat thews, M.: Nelp, W.B.; Sisom, K..; Chesnut C.H.. Ill: Long term calcitonin therapy in post menopausal osteoporosis. Metabolism 33: 295-303(1984). 7 Overgaard, K..; Riis, B.J.; Christiansen, C ; Hansen, M.A.: Effect of Salcatonin given intranasally on early postmenopausal bone loss. Br. med.j. 299:477-479(1989). 8 Mac Intyre, I.; Stevenson, J.C.; Whitehead, M.I.: Wimalanasa. S.J.; Banks, L.M.; Healy, M.J.R.: Calcitonin for prevention of post menopausal bone loss. Lancet i: 900-902 (1988).
9 Reginster, J.V.; Denis. D.; Albert. A.; Deroisy. R.; Lecart, M.P.; Fontaine. M.A.; Lambclin, P.; Franchimont, P.: 1-year controlled random ized trial of prevention of early post-menopausal bone loss by intranasal calcitonin. Lancet ii: 1481-1483(1987). 10 Gennari, C.; Passeri, M.: Chierichetti, S.M.; Piolini. M.: Side effects of synthetic salmon and human calcitonin. Lancet 594-595 (1983). 11 Nilas, L.; Norgaard, H.; Podenphant, J.; Godfredsen. A.; Christiansen, C.: Bone composi tion in the distal forearm. Scand J. clin. Lab. Invest. 47:41-46(1987). 12 Genant, H.K.; Cann, C.E.; Ettinger, B.; Gordan. G.S.: Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann. intern. Med. 97:699-705 (1982).
171
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1 Christiansen, C.: Intranasal calcitonin for pre vention and treatment of osteoporosis. Annls Chir. Gynaec. 77:229-234 (1988). 2 Overgaard. K.: Hansen, M.A.; Herss Nielsen. V. A.; Riis, B.J.; Christiansen, K.: Discontin uous calcitonin treatment of established osteo porosis. Effects of withdrawal of treatment. Am. J. Med. S9. 1-6(1990). 3 Chcsnut, C.H.. Ill; Baylink. D.J.; Roos. B.A.; Gruber. H.E.; Ivey, J.L.; Matthews, M.; Nelp. W. B.; Sisom, K.: Calcitonin and postmeno pausal osteoporosis; in Pecile, Calcitonin 1980. pp. 247-255 (Excerpta Medica, Amsterdam 1981). 4 Gennari, C.; Chierichetti, S.M.; Bigazzi, S.; Fusi, L.; Gonelli, S.; Ferrara, R.; Zacchei. F.: Comparative effects on bone mineral content of calcium and calcium plus salmon calcitonin given in two different regimens in postmeno pausal osteoporosis. Curr. ther. Res. 38: 455464(1985).
Clinic of Obstetrics and Gynecology, University of Rome ‘La Sapienza’, Policlinico Umberto I, Rome, Italy
Keywords Intranasal calcitonin Bone density Menopause Osteoporosis
Intranasal Salmon Calcitonin in Postmenopausal Osteoporosis: Effect of Different Therapeutic Regimens on Vertebral and Peripheral Bone Density
Abstract Sixty postmenopausal women were randomly assigned to three types of treat ment with intranasal salmon calcitonin (SCT) plus calcium 500 mg daily (group A: 100IU daily of SCT; group B: 100 IU daily of SCT for alternate cycles of 2 months with a 1-month interval; group C: 100 IU daily of SCT for alternate cycles of 3 months of treatment followed by a 3-month interval) or calcium 500 mg daily alone (control group). Lumbar density significantly decreased in the control group while it maintained the initial value in both continuously or cyclically treated groups. The bone density of the proximal and distal forearm in treated and control groups did not show significant changes after 12 months.
Introduction Several clinical studies have documented the efficacy of calcitonin in the treatment of postmenopausal osteo porosis; results generally show either a suppression of bone loss [1, 2] or an increment in bone mass [3-6]. The treatment with calcitonin also has a place in the pre vention of postmenopausal osteoporosis in women in whom estrogens are not indicated. Calcitonin administra tion, whether injective or intranasal, proved to be effi cient in the reduction in bone loss in healthy postmeno pausal women when compared to nontreated controls [79], Moreover, the improvement in both acceptability and compliance obtained with intranasal calcitonin enables its long-term use [9, 10]. Some controversies concerning
Received: August 26. 1991 Accepted: September 19.1991
the minimum effective dose for the prevention and the efficacy of the different forms of treatment (cyclic or continuative) are still being debated. The aim of our prospective 1-year randomized con trolled study is to verify the effect of different therapeutic regimens of intranasal salmon calcitonin (SCT) on verte bral and radial bone density in healthy postmenopausal women.
Materials and Methods Sixty postmenopausal women were included in the study. All had referred themselves to the menopausal clinic for an occasional check up. The patients were all between 52 and 60 years of age and had been in natural menopause for 2-5 years. None had received hor-
G. Perrone Clinic of Obstetrics and Gynecology University o f Rome ‘La Sapienza' Policlinico Umberto 1.1— 00199 Rome (Italy)
© 1992 S. Kargcr AG. Basel 0378-7346/92/0333-0168 $2.75/0
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
G. Perrone P. Galoppi M. Valente O. Capri C. D ’Ubaldo G. Anelli L. Zichella
Age, years
Group A
Group B
Group C
Controls
55±3
54 + 2
55 + 4
56 ± 3
4± 1
4±2
3± 1
Years after menopause
3± 1
Height, cm
161 ± 7
159 ± 6
160 ± 7
161 ± 5
Weight, kg
65±4
63 ± 5
64 ± 3
65 ± 5
Proximal forearm BMD, g/cm 2
0.584 ±0.78
0.583 ±0.38
0.553±0.39
0.589 ±0.43
Distal forearm, BMD, g/cm 2
0.467 ±0.38
0.438 ±0.65
0.427 ±0.57
0.470 ±0.61
L 2-L 4 BMD. g/cm 2
0.779 ±0.85
0.732 ±0.78
0.748 ±0.71
0.775 ±0.56
monal treatment nor taken any drug active on bone metabolism for at least 1 year before the study. Three types of treatment were ran domly assigned: group A: 100IU daily of intranasal SCT for 1 year plus calcium 500 mg daily (n = 15); group B: 100 IU daily of intra nasal SCT for alternate cycles of 2 months with a 1-month interval plus calcium 500 mg daily (n= 15), and group C: 100 IU daily of SCT spray for alternate cycles of 3 months of treatment followed by a 3-month interval plus calcium 500 mg daily (n = 15). A control group (n = 15), homogeneous in age and in menopausal stage, received calcium alone. The study period was 1 year. The bone mineral density o f the forearm was measured every 6 months by single photon absorptiom etry with a source of iodine-125 (Norland 2780) in the proximal and distal sites. The trabecular bone contents of these regions are approx imately 13 and 55%, respectively [11]. The bone density of the lum bar spine (L2-L4) was measured every 6 months by dual photon Xray absorptiometry (Hologic QDR-X 1000). In our department, the long-term precision of the two techniques in vivo is 3 and 1%, respec tively. Bone mineral density was measured before treatment and every 6 months. The difference in the densities was expressed as a percentage of basal values. The averages were compared using Student’s t test for paired and unpaired data. The differences between groups were tested by one-way analysis of variance.
Results All patients in group A completed the treatment. Group B had 1 dropout (n = 14) due to climacteric symp toms that required treatment with estrogen. Group C had 3 dropouts (n = 12), 1 due to a poor compliance and 2 due to personal reasons. All subjects of the control group completed the study. The patients’ clinical data and the averages and standard deviations of the densities measured before treatment are indicated in table 1.
The densities at the radial and vertebral sites are homogeneous. Figures 1-3 show the mean changes in radial and spi nal bone mineral densities in the treated and control groups. No significant difference was found within each single group in radial and vertebral bone sites after 6 and 12 months. The vertebral bone mineral density of the con trol group decreased significantly after 12 months, while that of the treated women was constant. No significant difference was found between cyclical and continuous treatment.
Discussion Calcitonin administered intranasally for 1 year, con tinuously or cyclically, was well tolerated by the post menopausal women; no adverse reactions were reported and only few patients abandoned the treatment before the end of the study. Bone mineral density measured at the lumbar spine significantly decreased in the control group while it main tained the initial value in all treated groups. Therefore, calcitonin given intranasally, according to different thera peutic regimens, showed a maintenance effect on the ver tebral bone density. At the radius, both treated women and controls did not show significant changes after 12 months of observation. The well-known effect of the injective SCT in the pre vention of bone loss [8] has also been demonstrated by the intranasal SCT [7, 9], Only one study [7] showed that 100 IU per day of intranasal calcitonin administered for 2 years had different effects on the spine as compared to the radius in healthy postmenopausal women.
169
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
T a b le 1. Clinical data, lumbar and peripheral bone mineral density (BMD) of the treated postmenopausal women
(%> Proximal forearm bm d
Fig. 1. Mean (SD) changes in bone min eral density in distal forearm in postmeno pausal women treated with different regi mens of intranasal SCT. * = Group A: • = group B; o = group C; A = controls.
bm d
(%)
bm d
(%)
Fig. 2. Mean (SD) changes in bone min eral density in distal forearm in postmeno pausal women treated with different regi mens of intranasal SCT. * = Group A; • = group B; o = group C; A = controls.
L 2 - L4
170
Perrone/Galoppi/Valente/Capri/D'Ubaldo/ Anelli/Zichella
Effect of Different Regimens of Intranasal Calcitonin on Bone Density
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
Fig. 3. Mean (SD) changes in bone min eral density in L2-L4 in postmenopausal women treated with different regimens of intranasal SCT. * = Group A; • = group B; o = group C; A = controls.
Although our study refers to only 1 year of treatment, we can confirm a significant protective effect with respect to vertebral bone loss after 12 months, while showing no effect on the radius. The decrease in vertebral bone den sity is more precocious and rapid with comparison to the measurable changes in the other skeletal sites [12]: in fact, the changes of bone density after 12 months measured at the distal and proximal radius in both control and treated groups arc not significant. Since the vertebral fracture is one of the most impor tant consequences of postmenopausal osteoporosis, pre venting bone loss in the spine is a crucial aim. Although estrogen is the most efficient prevention, calcitonin has
proven to be a valid alternative. We have confirmed that 100 IU per day of intranasal SCT can prevent vertebral bone loss. Cyclical administration of calcitonin has proven to be an effective treatment for postmenopausal osteoporosis [10, 13]; according to our results, 100 IU of spray SCT administered for alternative cycles has effects similar to those obtained with the continuous administration in the prevention of bone loss. Such a result can be of relevance in considering the improvement of the compliance and the cost advantage that cyclical administration may have.
References 5 Mazzuoli, G.F.; Passeri, M.; Gennari, C.; Mini sole, S.; Antonelli, R.; Valtorta, C.; Palummeri, E.; Cervellin, G.F.; Gonelli, S.: Francini, G.: Effects of salmon calcitonin in postmenopausal osteoporosis: a controlled double-blind clinical study. Calif. Tissue Int. 38:3-8 (1986). 6 Gruber, H.E.; Ivey, J.L.; Baylink, D.J.; Mat thews, M.: Nelp, W.B.; Sisom, K..; Chesnut C.H.. Ill: Long term calcitonin therapy in post menopausal osteoporosis. Metabolism 33: 295-303(1984). 7 Overgaard, K..; Riis, B.J.; Christiansen, C ; Hansen, M.A.: Effect of Salcatonin given intranasally on early postmenopausal bone loss. Br. med.j. 299:477-479(1989). 8 Mac Intyre, I.; Stevenson, J.C.; Whitehead, M.I.: Wimalanasa. S.J.; Banks, L.M.; Healy, M.J.R.: Calcitonin for prevention of post menopausal bone loss. Lancet i: 900-902 (1988).
9 Reginster, J.V.; Denis. D.; Albert. A.; Deroisy. R.; Lecart, M.P.; Fontaine. M.A.; Lambclin, P.; Franchimont, P.: 1-year controlled random ized trial of prevention of early post-menopausal bone loss by intranasal calcitonin. Lancet ii: 1481-1483(1987). 10 Gennari, C.; Passeri, M.: Chierichetti, S.M.; Piolini. M.: Side effects of synthetic salmon and human calcitonin. Lancet 594-595 (1983). 11 Nilas, L.; Norgaard, H.; Podenphant, J.; Godfredsen. A.; Christiansen, C.: Bone composi tion in the distal forearm. Scand J. clin. Lab. Invest. 47:41-46(1987). 12 Genant, H.K.; Cann, C.E.; Ettinger, B.; Gordan. G.S.: Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann. intern. Med. 97:699-705 (1982).
171
Downloaded by: Univ. of California Santa Barbara 128.111.121.42 - 3/3/2018 11:57:44 PM
1 Christiansen, C.: Intranasal calcitonin for pre vention and treatment of osteoporosis. Annls Chir. Gynaec. 77:229-234 (1988). 2 Overgaard. K.: Hansen, M.A.; Herss Nielsen. V. A.; Riis, B.J.; Christiansen, K.: Discontin uous calcitonin treatment of established osteo porosis. Effects of withdrawal of treatment. Am. J. Med. S9. 1-6(1990). 3 Chcsnut, C.H.. Ill; Baylink. D.J.; Roos. B.A.; Gruber. H.E.; Ivey, J.L.; Matthews, M.; Nelp. W. B.; Sisom, K.: Calcitonin and postmeno pausal osteoporosis; in Pecile, Calcitonin 1980. pp. 247-255 (Excerpta Medica, Amsterdam 1981). 4 Gennari, C.; Chierichetti, S.M.; Bigazzi, S.; Fusi, L.; Gonelli, S.; Ferrara, R.; Zacchei. F.: Comparative effects on bone mineral content of calcium and calcium plus salmon calcitonin given in two different regimens in postmeno pausal osteoporosis. Curr. ther. Res. 38: 455464(1985).
