European Journal of Obstetrics & Gynecology and Reproductive Biology, 47 (1992) 53-57
53
0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01403
Effect of hormone replacement therapy and calcitonin on bone mass in postmenopausal women M. Meschia
a, M. Brincat
b, P. Barbacini a, M. Carena and P.G. Crosignani b
Maini a, R. Marri
a
a 2nd Department of Obstetrics and Gynecology, University of Milan, Milan, Italy; b University of Malta, Medical School, Malta (Accepted for publication 3 July 1992)
Summary A total of 104 postmenopausal women were randomly assigned to different therapeutic regimens: (a) calcitonin, (b) estrogen/ progestogen (HRT) plus calcitonin, (c) estrogen/ progestogen (HRT), (d) and the control group. The bone mass of the lumbar vertebrae of all patients was assessed with a dual beam photon absorptiometer (Norland GD 153). The 73 patients who completed the 1-yr study showed that postmenopausal bone loss could be prevented by either estrogen/progestogen (HRT) or calcitonin. In addition, the combination of hormone1 replacement therapy and calcitonin not only prevented postmenopausal bone loss but resulted in a significant 10% gain in bone mass (P < 0.001). HRT; Calcitonin; Bone loss
Introduction Osteoporosis is a skeletal disorder predominantly seen in postmenopausal women. The physiologically balanced coupling of bone formation and bone resorption ensures the skeleton’s integrity and renewal. Peak bone mass is reached in the fourth decade of life and in the postmenopausal years there is an accelerated bone loss: by the age of 79 a woman has lost 50% of her bone, while a man has lost only 25% by the age of 90 [ll. It is estimated that by the age of 65 some 40% of women will have had at least one
Correspondence to: M. Meschia, M.D., 2nd Department of Obstetrics and Gynecology, University of Milan, Via Commenda, 12, 20122 Milan, Italy.
osteoporotic fracture [21. This is due to a decline in bone organic matrix, the primary pathological event leading to osteoporosis [3]. Oral estrogen administration has been shown to arrest postmenopausal bone loss [4,5]. However, it has been suggested that estrogen treatment on its own will only reduce the risk of osteoporotic fractures by 50% [6]. This is probably because therapy is started too late or because the bone mass at the start of the menopause, in certain individuals, is within the low normal range. Like estrogen, calcitonin when used alone has also been shown to prevent postmenopausal bone loss [7,81. Calcitonin is an endogenous 32-amino acid polypeptide hormone which binds to specific receptors on osteoclasts, inhibiting bone resorption. Many treatment strategies have been developed for the management of postmenopausal bone loss, aimed
54
at maintaining bone mass. To date only limited efforts have been aimed at increasing bone mass. The aim of this study was to investigate the effects of combination therapy on postmenopausal bone loss. The effects of combined treatment of calcitonin (Elcatonin) and HRT (conjugated estrogens and medroxyprogesterone acetate) were compared with those of HRT (conjugated estrogens and medroxyprogesterone acetate) and of Elcatonin alone. All groups were then compared with an untreated control group. Elcatonin is a recently developed synthetic analogue of eel calcitonin, with a greater stability to change in pH and temperature than other calcitonins. Weight for weight, Elcatonin is more biologically active than other calcitonins; weight for weight, Elcatonin is as biologically active as salmon and natural eel calcitonin. Materials and Methods A total of 104 patients seen at the menopause out-patient clinic of our department were assigned, according to a randomization list prepared by the main investigator, to. one of the following treatment groups. The first (group A) was given 40 IU of Elcatonin (1 ampoule), i.m., twice a week. The second (group B) was given 40 IU of Elcatonin (1 ampoule), i.m., twice a week, and 1.25 mg oral conjugated estrogens per day, continuously, plus 10 mg medroxyprogestrone acetate per day, orally, for ten days every month. The third (group C) was given 1.25 mg oral conjugated estrogens per day, continuously, and 10 mg medroxyprogesterone acetate per day, for 10 days every month. The no treatment group was formed by women deemed suitable for the inclusion in the trial and with a good level of attendance to follow-up visits, even if not treated. All the patients were normal women who had had a natural menopause for at least 1 yr and not more than 10 years previously. Patients were recruited if they had clinical evidence of menopause supported by a high level of follicle-stimulating hormone (FSH value > 40 III/l). Patients were excluded from entering the study for any of the following reasons: they had been treated with sex steroids during the year preceding admission to
the study; they had severe hepatic, renal, cardiac or gastroenterologic diseases; they had inflammatory or degenerative osteomuscular diseases (Paget’s disease, osteomalacia, rheumatoid arthritis); they were alcoholics; they had neoplastic disease; or they had been treated with drugs affecting bone metabolism in the 4 weeks preceding the inclusion in the study. Patients were assessed at baseline and after 3, 6 and 12 months of study. The following information was obtained before random assignment to treatment: age, years since the onset of menopause, serum FSH levels, bone density of lumbar spine (L2 - I.41 by dual beam photon absorptiometry (Norland GD 1531, clinical examination and biochemistry assessment including: calcium, phosphate, alkaline phosphatase, creatinine, Hb, Htc, RBC, WBC. In the 3rd, 6th and 12th months, assessment of the lumbar spine by dual beam photon absorptiometry (Norland GD 153) was repeated. The densitometry was performed by a blind observer in the Department of Orthopaedics, University of Milan. The biochemistry assessment was repeated after 12 months. After testing for normal distribution, the data were analyzed by the Student t-test for paired data. Across-group comparisons were made at 0, 3, 6 and 12 months by one-way analysis of variance. Results In this report we present the results for 73 patients who completed 1 yr of follow-up (104 were originally admitted to the study and randomly assigned to one of the treatment groups). The high rate of drop-outs, close to 30%, is related to: the i.m. administration of ECT for such a long period; the persistance of menopausal symptoms in the control group as well as in the ECT group; unbearable side effects related to HRT (vaginal bleeding, mastalgia) or to’ ECT (nausea, flushing). Moreover, regarding the 31 patients who did not complete the study, it has to be taken into account that not all drop-outs were due to side effects but, mainly in getting full compliance from patients, especially since this involved a considerable amount of travelling (Ta-
5.5
TABLE I
TABLE II
Patients withdrawn from the study
Combined therapy study patient data
Group
No.
Scarce compliance
Side effects
Lost at follow-up
A B C D
7 9 4 11
2 6 2 5
3
2 3 _ 6
2 _
Group
No. of patients
Age(yr)
ble 1). Table 2 gives clinical data for women who entered the study. At baseline there were no statistically significant differences between groups for menopausal age and body mass index while the chronological age was different between group A and group C when compared with other treatment groups. The data indicate that women given the active drugs were well matched among them and with those in the control group. Table 3 shows the mean changes in spinal bone mass in each group during the study. The Elcatonin group (group A) bone mass did not change between baseline and 12 months: 0.821 0.841 g/cm2. In the HRT and Elcatonin group (group B), there was a significant mean increase in vertebral bone mass of 10% (P < 0.001) at the end of one year of therapy: 0.884 - 0.981 g/cm2. At the end of 1 yr the bone mass of the HRT group (group C) was significantly increased by a mean of 3.2% (P < 0.05): 0.823 - 0.849 g/cm2. Finally, the control group (group D) had a significant mean bone loss of 5% (P < 0.001) after 1 yr: 0.830 - 0.788 g/cm2.
(SD) Menopausal age (yr) (SD) Body mass index (SD)
A
B
C
D
26 55.1 (4.31
26 52 (5.1) 3.9 (3.4) 26 (2)
26 49.3 (4.8)
26 53.3 (41 3 (2.2) 25.6 (3.3)
(S::) 26.8 (3.1)
(s:3, 26.3 (2.7)
FSH was > 40 IU/I for all women.
Table 4 compares the results of different regimens at the end of 1 yr of therapy. Finally, all biochemical indexes considered were in the normal range at the beginning and at the end of the study. Discussion
Bone loss during the postmenopausal years is a general phenomenon and affects all parts of the skeleton [9]. However, cross-sectional [lo] and longitudinal studies by quantitative computed tomography, which measures the trabecular bone content exclusively [ll], have shown that bone loss from the spine exceeds that from peripheral bones, at least during the early postmenopausal years. The lumbar spine bears weight and many women with osteoporosis have evidence of one or more spinal crush fractures. Therefore, spinal bone mass measurements are of special clinical
TABLE III Bone mass changes after 1 yr Mean (SE) gm/cm2 Months 0 Elcatonin N= 19 Premarin + Elcatonin N=l7 Premarin N=22 Controls N= 15
0.82 (0.03) 0.88 (0.02) 0.82 (0.02) 0.83 (0.02)
* P < 0.05; * * P < 0.01; * * * P < 0.001.
3
6
12
0.88 * (0.03) 0.94 ** (0.03) 0.84 * (0.03)
0.84 (0.03) 0.96 ** (0.04) 0.86 ** (0.02)
0.84 (0.02) 0.98 *** (0.05) 0.85 * (0.02) 079 *** (0:02)
Change f%Ig) + 2.4 * +10 +3.2 -5
56 TABLE IV Comparison of effects of different regimens at the end of 1 yr * Regimen
Significance
P
Premarin vs controls Calcitonin vs controls Premarin + calcitonin vs controls Calcitonin vs Premarin Premarin + calcitonin vs Premarin Premarin + calcitonin vs calcitonin
S S S NS S S
< < < < <
for 5 days a week [12,13]. Undoubtedly, the estrogen treatment is strictly linked to this particular period of life, since all the menopausal symptoms (flushing vaginal atrophy) are well controlled by the hormonal replacement therapy. However, many patients may present contraindications to HRT (intravascular thrombosis liver disease, etc.), and the relationship between HRT and breast cancer should be carefully evaluated. Consequently, an alternative therapy has to be considered and calcitonin is one of the best assessed and well tolerated pharmacological compounds in the prevention and treatment of the osteoporotic syndrome. Moreover, estrogens and calcitonin, combined in adequate doses, not only prevent postmenopausal bone loss, but result in a significant gain. In our study, the mean gain was 10% after 1 yr. Whether or not the beneficial gain in bone mass, in the combined group of postmenopausal women, persists still needs to be assessed: if it
proves to be a long lasting effect, it would be logical to suggest this regimen for women who have an initial high rate of bone loss. The next step will be maintenance of the bone mass with either estrogen/ progestogen or calcitonin, depending on the overall picture of the woman concerned. The difference between the results of estrogens alone and estrogens plus calcitonin is quite clear. Our estrogen dose (1.25 mg> is not at present the usual one, but even low doses [14] have been shown to have similar sparing effects on bone mass. Obviously, we cannot rule out that the comparative effect of estrogen and calcitonin is a dose-dependent phenomenon. References 1 Gordan GS. Prevention of bone loss and fractures in women. Maturitas 1984;6:224-242. 2 Crilly RG, Horsman A, Marshall DH, Nordin BEC. Bone mass in postmenopausal women after withdrawal of oestrogen/gestogen replacement therapy. Lancet 1978;i: 459-461. 3 Brincat M, Moniz CJ, Kabalan S et al. Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. Br J Obstet Gynaecol 1987;94:126-129. Lindsay R, Hart DM, Purdee D, Ferguson M, Clark AS. Comparative effects of oestrogen and progestagen on bone loss in postmenopausal women. Clin. Sci. Molec. Med. 1978;54:193-198. Natchigall LE, Natchigall KH, Natchigall RD, Bechman E. Estrogen replacement therapy: a lo-year prospective study in the response to osteoporosis. Obstet Gynecol 1980;53:277-281. Ross RR, Paganini-Hill A, Mach JM. Reduction in fractures and other effects of estrogen replacement therapy in human population. In: Osteoporosis. Proc. of the Copenhagen Int. Symposium on Osteoporosis 1984;1:289-297. Reginster JY, Denis D, Albert R et al. P. l-year controlled randomized trial of prevention of early postmenopausal bone loss by intranasal c alcitonin. Lancet 1987;11:14811483. MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988;1:900-902. Riis BJ, Christiansen C. Measurement of spinal or peripheral bone mass to estimate early postmenopausal bone loss? Am J Med 1988;84:646-653. Riggs BL, Wahner HW, Dunn WL, Mazess RB, Offord KP, Melton LJ. Differential changes in bone mineral density of the appendicular and axial skeleton with aging. Relationship to spinal osteoporosis. J Clin Invest 1981; 67:328-335.
57 11 Genant HK, Cann CE, Ettinger B, Gordan GS. Quantita-
tive computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med 1982;97:699-705. 12 Reginster JY, Albert A, Franchimont P. Effect of nasal administration of synthetic salmon calcitonin in Paget’s
bone disease. Calcif Tiss Int 1985;37:577-580. 13 Reginster JY, Denis D, Albert A, Franchimont P. Assess-
ment of the biological effectiveness of nasal synthetic salmon calcitonin (SSCI’) by comparison with intramuscular (i.m.) or placebo injection in normal subjects. Bone Min 1987;2:133-140. 14 Lindsay R, Hart DM, Clark DN. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63:759-763.
53
0 1992 Elsevier Science Publishers B.V. All rights reserved 0028-2243/92/$05.00 EUROBS 01403
Effect of hormone replacement therapy and calcitonin on bone mass in postmenopausal women M. Meschia
a, M. Brincat
b, P. Barbacini a, M. Carena and P.G. Crosignani b
Maini a, R. Marri
a
a 2nd Department of Obstetrics and Gynecology, University of Milan, Milan, Italy; b University of Malta, Medical School, Malta (Accepted for publication 3 July 1992)
Summary A total of 104 postmenopausal women were randomly assigned to different therapeutic regimens: (a) calcitonin, (b) estrogen/ progestogen (HRT) plus calcitonin, (c) estrogen/ progestogen (HRT), (d) and the control group. The bone mass of the lumbar vertebrae of all patients was assessed with a dual beam photon absorptiometer (Norland GD 153). The 73 patients who completed the 1-yr study showed that postmenopausal bone loss could be prevented by either estrogen/progestogen (HRT) or calcitonin. In addition, the combination of hormone1 replacement therapy and calcitonin not only prevented postmenopausal bone loss but resulted in a significant 10% gain in bone mass (P < 0.001). HRT; Calcitonin; Bone loss
Introduction Osteoporosis is a skeletal disorder predominantly seen in postmenopausal women. The physiologically balanced coupling of bone formation and bone resorption ensures the skeleton’s integrity and renewal. Peak bone mass is reached in the fourth decade of life and in the postmenopausal years there is an accelerated bone loss: by the age of 79 a woman has lost 50% of her bone, while a man has lost only 25% by the age of 90 [ll. It is estimated that by the age of 65 some 40% of women will have had at least one
Correspondence to: M. Meschia, M.D., 2nd Department of Obstetrics and Gynecology, University of Milan, Via Commenda, 12, 20122 Milan, Italy.
osteoporotic fracture [21. This is due to a decline in bone organic matrix, the primary pathological event leading to osteoporosis [3]. Oral estrogen administration has been shown to arrest postmenopausal bone loss [4,5]. However, it has been suggested that estrogen treatment on its own will only reduce the risk of osteoporotic fractures by 50% [6]. This is probably because therapy is started too late or because the bone mass at the start of the menopause, in certain individuals, is within the low normal range. Like estrogen, calcitonin when used alone has also been shown to prevent postmenopausal bone loss [7,81. Calcitonin is an endogenous 32-amino acid polypeptide hormone which binds to specific receptors on osteoclasts, inhibiting bone resorption. Many treatment strategies have been developed for the management of postmenopausal bone loss, aimed
54
at maintaining bone mass. To date only limited efforts have been aimed at increasing bone mass. The aim of this study was to investigate the effects of combination therapy on postmenopausal bone loss. The effects of combined treatment of calcitonin (Elcatonin) and HRT (conjugated estrogens and medroxyprogesterone acetate) were compared with those of HRT (conjugated estrogens and medroxyprogesterone acetate) and of Elcatonin alone. All groups were then compared with an untreated control group. Elcatonin is a recently developed synthetic analogue of eel calcitonin, with a greater stability to change in pH and temperature than other calcitonins. Weight for weight, Elcatonin is more biologically active than other calcitonins; weight for weight, Elcatonin is as biologically active as salmon and natural eel calcitonin. Materials and Methods A total of 104 patients seen at the menopause out-patient clinic of our department were assigned, according to a randomization list prepared by the main investigator, to. one of the following treatment groups. The first (group A) was given 40 IU of Elcatonin (1 ampoule), i.m., twice a week. The second (group B) was given 40 IU of Elcatonin (1 ampoule), i.m., twice a week, and 1.25 mg oral conjugated estrogens per day, continuously, plus 10 mg medroxyprogestrone acetate per day, orally, for ten days every month. The third (group C) was given 1.25 mg oral conjugated estrogens per day, continuously, and 10 mg medroxyprogesterone acetate per day, for 10 days every month. The no treatment group was formed by women deemed suitable for the inclusion in the trial and with a good level of attendance to follow-up visits, even if not treated. All the patients were normal women who had had a natural menopause for at least 1 yr and not more than 10 years previously. Patients were recruited if they had clinical evidence of menopause supported by a high level of follicle-stimulating hormone (FSH value > 40 III/l). Patients were excluded from entering the study for any of the following reasons: they had been treated with sex steroids during the year preceding admission to
the study; they had severe hepatic, renal, cardiac or gastroenterologic diseases; they had inflammatory or degenerative osteomuscular diseases (Paget’s disease, osteomalacia, rheumatoid arthritis); they were alcoholics; they had neoplastic disease; or they had been treated with drugs affecting bone metabolism in the 4 weeks preceding the inclusion in the study. Patients were assessed at baseline and after 3, 6 and 12 months of study. The following information was obtained before random assignment to treatment: age, years since the onset of menopause, serum FSH levels, bone density of lumbar spine (L2 - I.41 by dual beam photon absorptiometry (Norland GD 1531, clinical examination and biochemistry assessment including: calcium, phosphate, alkaline phosphatase, creatinine, Hb, Htc, RBC, WBC. In the 3rd, 6th and 12th months, assessment of the lumbar spine by dual beam photon absorptiometry (Norland GD 153) was repeated. The densitometry was performed by a blind observer in the Department of Orthopaedics, University of Milan. The biochemistry assessment was repeated after 12 months. After testing for normal distribution, the data were analyzed by the Student t-test for paired data. Across-group comparisons were made at 0, 3, 6 and 12 months by one-way analysis of variance. Results In this report we present the results for 73 patients who completed 1 yr of follow-up (104 were originally admitted to the study and randomly assigned to one of the treatment groups). The high rate of drop-outs, close to 30%, is related to: the i.m. administration of ECT for such a long period; the persistance of menopausal symptoms in the control group as well as in the ECT group; unbearable side effects related to HRT (vaginal bleeding, mastalgia) or to’ ECT (nausea, flushing). Moreover, regarding the 31 patients who did not complete the study, it has to be taken into account that not all drop-outs were due to side effects but, mainly in getting full compliance from patients, especially since this involved a considerable amount of travelling (Ta-
5.5
TABLE I
TABLE II
Patients withdrawn from the study
Combined therapy study patient data
Group
No.
Scarce compliance
Side effects
Lost at follow-up
A B C D
7 9 4 11
2 6 2 5
3
2 3 _ 6
2 _
Group
No. of patients
Age(yr)
ble 1). Table 2 gives clinical data for women who entered the study. At baseline there were no statistically significant differences between groups for menopausal age and body mass index while the chronological age was different between group A and group C when compared with other treatment groups. The data indicate that women given the active drugs were well matched among them and with those in the control group. Table 3 shows the mean changes in spinal bone mass in each group during the study. The Elcatonin group (group A) bone mass did not change between baseline and 12 months: 0.821 0.841 g/cm2. In the HRT and Elcatonin group (group B), there was a significant mean increase in vertebral bone mass of 10% (P < 0.001) at the end of one year of therapy: 0.884 - 0.981 g/cm2. At the end of 1 yr the bone mass of the HRT group (group C) was significantly increased by a mean of 3.2% (P < 0.05): 0.823 - 0.849 g/cm2. Finally, the control group (group D) had a significant mean bone loss of 5% (P < 0.001) after 1 yr: 0.830 - 0.788 g/cm2.
(SD) Menopausal age (yr) (SD) Body mass index (SD)
A
B
C
D
26 55.1 (4.31
26 52 (5.1) 3.9 (3.4) 26 (2)
26 49.3 (4.8)
26 53.3 (41 3 (2.2) 25.6 (3.3)
(S::) 26.8 (3.1)
(s:3, 26.3 (2.7)
FSH was > 40 IU/I for all women.
Table 4 compares the results of different regimens at the end of 1 yr of therapy. Finally, all biochemical indexes considered were in the normal range at the beginning and at the end of the study. Discussion
Bone loss during the postmenopausal years is a general phenomenon and affects all parts of the skeleton [9]. However, cross-sectional [lo] and longitudinal studies by quantitative computed tomography, which measures the trabecular bone content exclusively [ll], have shown that bone loss from the spine exceeds that from peripheral bones, at least during the early postmenopausal years. The lumbar spine bears weight and many women with osteoporosis have evidence of one or more spinal crush fractures. Therefore, spinal bone mass measurements are of special clinical
TABLE III Bone mass changes after 1 yr Mean (SE) gm/cm2 Months 0 Elcatonin N= 19 Premarin + Elcatonin N=l7 Premarin N=22 Controls N= 15
0.82 (0.03) 0.88 (0.02) 0.82 (0.02) 0.83 (0.02)
* P < 0.05; * * P < 0.01; * * * P < 0.001.
3
6
12
0.88 * (0.03) 0.94 ** (0.03) 0.84 * (0.03)
0.84 (0.03) 0.96 ** (0.04) 0.86 ** (0.02)
0.84 (0.02) 0.98 *** (0.05) 0.85 * (0.02) 079 *** (0:02)
Change f%Ig) + 2.4 * +10 +3.2 -5
56 TABLE IV Comparison of effects of different regimens at the end of 1 yr * Regimen
Significance
P
Premarin vs controls Calcitonin vs controls Premarin + calcitonin vs controls Calcitonin vs Premarin Premarin + calcitonin vs Premarin Premarin + calcitonin vs calcitonin
S S S NS S S
< < < < <
for 5 days a week [12,13]. Undoubtedly, the estrogen treatment is strictly linked to this particular period of life, since all the menopausal symptoms (flushing vaginal atrophy) are well controlled by the hormonal replacement therapy. However, many patients may present contraindications to HRT (intravascular thrombosis liver disease, etc.), and the relationship between HRT and breast cancer should be carefully evaluated. Consequently, an alternative therapy has to be considered and calcitonin is one of the best assessed and well tolerated pharmacological compounds in the prevention and treatment of the osteoporotic syndrome. Moreover, estrogens and calcitonin, combined in adequate doses, not only prevent postmenopausal bone loss, but result in a significant gain. In our study, the mean gain was 10% after 1 yr. Whether or not the beneficial gain in bone mass, in the combined group of postmenopausal women, persists still needs to be assessed: if it
proves to be a long lasting effect, it would be logical to suggest this regimen for women who have an initial high rate of bone loss. The next step will be maintenance of the bone mass with either estrogen/ progestogen or calcitonin, depending on the overall picture of the woman concerned. The difference between the results of estrogens alone and estrogens plus calcitonin is quite clear. Our estrogen dose (1.25 mg> is not at present the usual one, but even low doses [14] have been shown to have similar sparing effects on bone mass. Obviously, we cannot rule out that the comparative effect of estrogen and calcitonin is a dose-dependent phenomenon. References 1 Gordan GS. Prevention of bone loss and fractures in women. Maturitas 1984;6:224-242. 2 Crilly RG, Horsman A, Marshall DH, Nordin BEC. Bone mass in postmenopausal women after withdrawal of oestrogen/gestogen replacement therapy. Lancet 1978;i: 459-461. 3 Brincat M, Moniz CJ, Kabalan S et al. Decline in skin collagen content and metacarpal index after the menopause and its prevention with sex hormone replacement. Br J Obstet Gynaecol 1987;94:126-129. Lindsay R, Hart DM, Purdee D, Ferguson M, Clark AS. Comparative effects of oestrogen and progestagen on bone loss in postmenopausal women. Clin. Sci. Molec. Med. 1978;54:193-198. Natchigall LE, Natchigall KH, Natchigall RD, Bechman E. Estrogen replacement therapy: a lo-year prospective study in the response to osteoporosis. Obstet Gynecol 1980;53:277-281. Ross RR, Paganini-Hill A, Mach JM. Reduction in fractures and other effects of estrogen replacement therapy in human population. In: Osteoporosis. Proc. of the Copenhagen Int. Symposium on Osteoporosis 1984;1:289-297. Reginster JY, Denis D, Albert R et al. P. l-year controlled randomized trial of prevention of early postmenopausal bone loss by intranasal c alcitonin. Lancet 1987;11:14811483. MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJR. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988;1:900-902. Riis BJ, Christiansen C. Measurement of spinal or peripheral bone mass to estimate early postmenopausal bone loss? Am J Med 1988;84:646-653. Riggs BL, Wahner HW, Dunn WL, Mazess RB, Offord KP, Melton LJ. Differential changes in bone mineral density of the appendicular and axial skeleton with aging. Relationship to spinal osteoporosis. J Clin Invest 1981; 67:328-335.
57 11 Genant HK, Cann CE, Ettinger B, Gordan GS. Quantita-
tive computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med 1982;97:699-705. 12 Reginster JY, Albert A, Franchimont P. Effect of nasal administration of synthetic salmon calcitonin in Paget’s
bone disease. Calcif Tiss Int 1985;37:577-580. 13 Reginster JY, Denis D, Albert A, Franchimont P. Assess-
ment of the biological effectiveness of nasal synthetic salmon calcitonin (SSCI’) by comparison with intramuscular (i.m.) or placebo injection in normal subjects. Bone Min 1987;2:133-140. 14 Lindsay R, Hart DM, Clark DN. The minimum effective dose of estrogen for prevention of postmenopausal bone loss. Obstet Gynecol 1984;63:759-763.
