Calcif Tissue Int (1991) [Suppl] 49:$60-$63
Calcified Tissue International 9 1991 Springer-Verlag New York Inc.
Long-Term Treatment of Established Osteoporosis with Intranasal Calcitonin Kirsten Overgaard and Claus Christiansen Department of Clinical Chemistry, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark
Summary. We examined the long-term effects of intranasal administration of salmon calcitonin on bone and calcium metabolism in women with established osteoporosis (forearm fracture). Over a period of 5 years, 14 women received discontinuous calcitonin (200 IU) plus calcium (500 mg) daily for 3 years or 4 years. To allow assessment of the optimum duration of therapy, patients in whom treatment had been for shorter intervals were also included. At the end of the first 2 years, a group receiving placebo had lost significantly more bone from their spines and forearms than the group receiving calcitonin in the first year (P < 0.01). In the 14 women who completed a further 3 years on calcitonin, the bone mineral contents of the spines increased continually. Bone loss in the forearm was arrested for 1 year. Treatment lasting for about 2 years prevented bone loss in both areas. Treatment for 3 years resulted in net gains in spinal bone but no further benefits in relation to forearms. Biochemical parameters of bone turnover (serum alkaline phosphatase levels, plasma bone Gla p r o t e i n l e v e l s , and fasting u r i n a r y h y d r o x y proline/creatinine levels) exhibited similar declines irrespective of the duration of treatment. It is concluded that longterm intranasal treatment with calcitonin produced net gains in spinal bone and that optimum response in forearms was achieved using discontinuous therapy. The ratio between periods with and without treatment was between 1:2 and 2:3.
Key words: Calcitonin - Osteoporosis - Bone mineral content.
Recent studies have indicated that intranasal sCT may be useful for the treatment of osteoporosis [5, 6], but its longterm effects remain to be determined. In the study reported here long-term effects of intranasal sCT in 14 postmenopausal women with osteoporosis were assessed and the optimum duration of discontinuous treatment evaluated.
Materials and Methods Subjects and Study Design Fourteen women with osteoporosis (forearm fracture following minor trauma) took part in a 5-year study of intranasal calcitonin therapy. In the first 3 years, the women participated in two larger studies [5, 6], carried out using different designs (Table 1). The first, a double-blind study [5] ran for 1 year. In it, eight of the women received sCT (200 IU) intranasally and calcium (500 mg) every day. The other six women received placebo and calcium. No treatment was given in the second year. In the third year, a follow-up study [6] was conducted. An open design was used. All 14 women received 200 IU sCT intranasally and 500 mg calcium each day. The open design study continued for 2 years. Over a period of 5 years, eight women therefore received active treatment for 4 years, six women for 3 years. To allow the optimum interval for therapy to be assessed some data from the first two studies [5, 6] were used in the study reported here.
Measurements of Bone Mass As people live longer, age-related diseases increasingly present problems. Osteoporosis is a major age-related disease affecting millions of people throughout the world, especially women. It is characterized by decreased amount of bone and increased susceptibility to fracture. It is not yet certain whether or not there is any effective treatment once osteoporosis has been diagnosed. Calcitonin is involved in calcium homeostasis. Its main target organ is the skeleton. Calcitonin rapidly inhibits osteoclast activity [ 1] and decreases the plasma concentrations of calcium if bone turnover is high. In the long term, it affects the number of osteoclasts by inhibiting production of osteoclast precursor [2]. Injectable calcitonin has been approved for treatment of osteoporosis in the United States following a controlled trial in which total body calcium was shown to increase significantly in a group receiving salmon calcitonin (sCT) but to fall in a control group [3]. A double-blind study showed that an injection of sCT (100 IU) on alternate days increased forearm bone mineral content [4]. Development of an intranasal dosage form has made long-term therapy more convenient.
Bone mineral content (BMC) of the forearm was measured by single photon absorptiometry (SPA), using a 125I source (3.7 GBq) with a photopeak at 27 KeV. The method determines BMC in the proximal region (BMCarm) as the mean of six scans 4 mm apart just proximal to a site at which the distance between the ulna and the radius is 8 mm. The long-term precision in vivo is 1% [7]. Measurements were performed every 3 months for the first 3 years and every 6 months for the remaining 2 years. The BMC of the lumbar spine (BMCspine) was measured using dual photon absorptiometry (DPA), a DP3 scanner (Lunar Radiation), and a 1530 Gd source (37 GBq) with photopeaks at 44 and 100 KeV. The BMCspi,e was calculated for vertebrae L2 to L4, including intervertebral discs. The long-term precision in vivo for BMCspine is 3.4% after correcting for errors caused by replacement of the source [7, 8]. Measurements were performed once a year for the first 3 years and every 6 months for the last 2 years.
Measurements of Bone Turnover Blood samples were taken and urine was collected in the morning, after overnight fasting and abstinence from tobacco. Serum alkaline
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
$61
Table 1. Study design, clinical data, and initial bone mass measurements (mean • SD) relating to the 14 women who completed the 5-year observation period
Year 1 Year 2 Year 3 Year 4-5
Study design
Number of participants
Placebo-controlled No treatment Open follow-up Open follow-up
17 nasal sCT 17 15 nasal sCT 8 nasal sCT
20 placebo 12 11 nasal sCT 6 nasal sCT
(n = 8)
(n = 6)
Initial data (n = 14) Age (years) Menopausal age (years) Height (cm) Weight (kg) BMCarm (units) BMCspine (g)
phosphatase (sAP) was measured enzymatically according to Scandinavian recommendations [9]. The coefficient of variation was 5%. Plasma bone Gla protein (pBGP) was measured using radioimmunoassay. Intra- and interassay variations were less than 7% and 12% [10]. These results indicate bone formation. Fasting urinary hydroxyproline levels were measured by spectrophotometry [11] and corrected for creatinine excretion (FuHpr/Cr). The intra- and interassay variations were about 10% and 13%. This parameter is an indicator of bone resorption. Measurements were performed every 3 months for the first 3 years and every 6 months for the last 2 years. To eliminate interassay variations of pBGP and FuHpr, samples from each woman were analyzed in the same assays.
Statistical Analysis Pretreatment values were taken to be 100. All subsequent measurements were expressed as percentages of these values, Changes in bone mass with time found through yearly measurements were expressed as percentages of pretreatment values. For measurements performed every 3 and 6 months, average annual changes in bone mass and turnover were calculated on values cumulated since the start of treatment [12]. Changes during the first 2 years were recorded as mean values for each bone compartment in the group receiving 1 year of placebo treatment plus calcium followed by 1 year without treatment. Changes during the 3-year open study were expressed as percentages of the measurements before the period of calcitonin therapy. To allow the optimum therapy interval to be assessed, responses in relation to bone mass and bone turnover were calculated for the various intervals, using values for all participants who had received calcitonin during these intervals. The durations of the intervals were expressed as percentages of the period of observation. The maximum period of treatment was 4 years, since there had been 1 year without treatment. The maximum interval without treatment was 2 years. Changes which would have occurred over a 5-year period were estimated by extrapolation. The significances of differences in changes within groups during the various intervals were tested using Student's t test for paired data.
Results
Table 1 shows the numbers of participants completing the various treatment periods during the observation period. Table 1 also shows clinical data relating to the 14 women studied for the full 5 years and baseline values for BMC measurements. The two groups were well matched. Figure 1 shows changes in BMCspine over 5 years. At the
65.6 • 6.6 19.0 • 160.9 70.4 • 28.2 • 35.3 •
7.3 4.5 8.2 3.3 5.6
59.7 • 2.9 12.3 162.6 73.4 31.2 37.3
• 6.4 --- 5.6 • 15.8 • 4.3 --- 4.5
end of the first 2 years, the group receiving placebo for 1 year had experienced a bone loss of 6.4%, significantly different from the response in the group receiving calcitonin for 1 year (P < 0.01). The same pattern was seen in relation to BMCar m. In the 14 women who completed another 3 years on calcitonin therapy, the BMCspi,e showed an increase after 1 year, which persisted throughout the observation period. Calcitonin administration prevented further declines in BMCar m during the first year, after which the response levelled off. Figure 2 shows responses of BMCspln ~ and BMC~m to different periods of calcitonin therapy. Treatment for about 2 years prevented bone loss in both compartments. A net gain in BMCspin e was attained by extending treatment to 3 years. No further benefit was seen in relation to BMC~rm. Figure 3 shows the effects of various periods of calcitonin therapy on biochemical indicators of bone turnover. The decline in sAP was independent of the duration of treatment. The same pattern was seen for pBGP and FuHpr/Cr.
Discussion
Estrogen replacement is considered to be specific therapy for accelerated bone loss after the menopause [13] and can be instituted at any time after the menopause. If therapy is started early enough, it will prevent fractures of the hip, spine, and distal forearm. Since many women find it inconvenient to start estrogen therapy some years after the menopause, calcitonin administration is an alternative treatment for osteoporosis. The women in the study reported here exhibited moderate degrees of osteoporosis, with average bone losses of 25% to 30% as compared with premenopausal values. They were selected at random from a representative sample and were well matched as regards initial parameters. The study shows that intranasal administration of calcitonin prevented bone loss in women with osteoporosis and that long-term therapy was especially effective in relation to the spine. The effect of calcitonin administration on calcium metabolism has been reported to reach a plateau and even to cease [3]. The exact mechanisms of these phenomena have not yet been clarified, but receptor down-regulation and formation of antibodies have been suggested [14, 15]. In our study, a plateau effect followed by cessation of action was observed in relation to forearms but not to spines. This might indicate that receptors in forearms and spines have different
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
$62 BiCspine
0
-4
-8 I
I
I
I
I
I
0
1
2
,3
4
5
I
1.o traa,m..,I
1F %
o -8
.as., o,,,o,,on,n
Fig. 1. Changes in bone mineral content of the lumbar spine BMCspi,r after different treatment periods. Left: Mean decrease in BMCspine over 2 years after 1 year of placebo therapy. Right: Changes in BMCsp~,e in relation to 3 years of calcitonin therapy.
years
I
~
BMCspine
sAP
%
,T,T
_L
-20
-16
-40 %
Treatment
BMCarm
33
50
67
75
80
1/3
2/4
2/3
3/4
4/5
% years/years
Fig. 3. Response (mean _+ SEM) in terms of serum alkaline phosphatase (sAP) in relation to duration of calcitonin therapy.
~1
-4
uous administration obviously reduces costs of long-term therapy.
-8
0
33
50
67
75
80
%
0/5
1/3
2/4
2/3
3/4
4/5
years/years
Treatment
Fig. 2. Response (mean -+ SEM) in terms of bone mineral content of the lumbar spine (BMCspine)and of the forearm (BMCarm)in relation to duration of calcitonin therapy.
sensitivities to calcitonin, resulting in earlier receptor downregulation in one bone compartment than in the other. This could occur to a greater extent in the forearm because bone turnover there, i.e., the difference between bone formation and bone resorption, is low compared with that in the spine. This supposition is supported by the more prolonged response in the spine and the continuous decline on parameters reflecting bone turnover. Our study indicates that discontinuous intranasal treatment with calcitonin affects bone and calcium metabolism in women with osteoporosis and that the optimum ratio between periods with and without treatment is between 1:2 and 2:3. From the results of the study it is concluded that longterm intranasal treatment with calcitonin is particularly effective in relation to the spine, where a net gain in bone was seen, and that the optimum response in relation to the forearm is achieved using discontinuous therapy. Discontin-
References 1. Singer FR, Melvin KEW, Mills BG (1976) Acute effects of calcitonin on osteoclasts in man. Clin Endocrinol 5:333-340 2. Hedlund T, Hulth A, Johnell O (1983) Early effects ofparathormone and calcitonin on the number of osteoclasts and on serum calcium in rats. Acta Orthop Scand 54:802-804 3. Gruber HE, Ivey JL, Baylink DJ, Matthews M, Nelp WB, Sisom K, Chesnut III CH (1984) Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 33:295-303 4. Mazzuoli GF, Passeri M, Gennari C, Minisola S, Antonelli R, Valtorta C, Palummeri E, Cervellin GF, Gonnelli S, Francini G (1986) Effects of salmon calcitonin in postmenopausal osteoporosis: a controlled double-blind clinical study. Calcif Tissue Int 38:3-8 5. Overgaard K, Riis BJ, Christiansen C, PCdenphant J, Johansen JS (1989) Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 30:435-443 6. Overgaard K, Hansen MA, Nielsen V-AH, Riis BJ, Christiansen C (1990) Discontinuous calcitonin treatment of established osteoporosis---effects of withdrawal of treatment. Am J Med 89:1-6 7. Nilas L, Borg J, Gotfredsen A, Christiansen C (1985) Comparison of single- and dual-photon absorptiometry in postmenopausal bone mineral loss. J Nucl Med 26:1257-1262 8. Nilas L, Hassager C, Christiansen C (1988) Long-term precision
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
9.
10.
11.
12.
of dual photon absorptiometry in the lumbar spine in clinical settings. Bone Miner 3:305-315 The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology (1974) Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33:291-306 Johansen JS, Mr Hansen JE, Christiansen C (1987) A radioimmunoassay for bone Gla protein (BGP) in human plasma. Acta Endocrinol 114:410-416 Pedenphant J, Larsen N-E, Christiansen C (1984) An easy and reliable method for determination of urinary hydroxyproline. Clin Chim Acta 142:145-148 Matthews JNS, Altman DG, Campbell MJ, Royston P (1990)
$63 Analysis of serial measurements in medical research. Br Med J 300:230-235 13. Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund K-E, Transbr I (1980) Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest 10:273-279 14. Bouizar Z, Rost~ne WH, Milhaud G (1987) Down-regulation of rat kidney calcitonin receptors by salmon calcitonin infusion evidenced by autoradiography. Proc Natl Acad Sci USA 84:5125-5128 15. Levy F, Muff R, Dotti-Sigrist S, Dambacher MA, Fischer JA (1988) Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease. J Clin Endocrinol Metab 67:541-545
Calcified Tissue International 9 1991 Springer-Verlag New York Inc.
Long-Term Treatment of Established Osteoporosis with Intranasal Calcitonin Kirsten Overgaard and Claus Christiansen Department of Clinical Chemistry, Glostrup Hospital, University of Copenhagen, DK-2600 Glostrup, Denmark
Summary. We examined the long-term effects of intranasal administration of salmon calcitonin on bone and calcium metabolism in women with established osteoporosis (forearm fracture). Over a period of 5 years, 14 women received discontinuous calcitonin (200 IU) plus calcium (500 mg) daily for 3 years or 4 years. To allow assessment of the optimum duration of therapy, patients in whom treatment had been for shorter intervals were also included. At the end of the first 2 years, a group receiving placebo had lost significantly more bone from their spines and forearms than the group receiving calcitonin in the first year (P < 0.01). In the 14 women who completed a further 3 years on calcitonin, the bone mineral contents of the spines increased continually. Bone loss in the forearm was arrested for 1 year. Treatment lasting for about 2 years prevented bone loss in both areas. Treatment for 3 years resulted in net gains in spinal bone but no further benefits in relation to forearms. Biochemical parameters of bone turnover (serum alkaline phosphatase levels, plasma bone Gla p r o t e i n l e v e l s , and fasting u r i n a r y h y d r o x y proline/creatinine levels) exhibited similar declines irrespective of the duration of treatment. It is concluded that longterm intranasal treatment with calcitonin produced net gains in spinal bone and that optimum response in forearms was achieved using discontinuous therapy. The ratio between periods with and without treatment was between 1:2 and 2:3.
Key words: Calcitonin - Osteoporosis - Bone mineral content.
Recent studies have indicated that intranasal sCT may be useful for the treatment of osteoporosis [5, 6], but its longterm effects remain to be determined. In the study reported here long-term effects of intranasal sCT in 14 postmenopausal women with osteoporosis were assessed and the optimum duration of discontinuous treatment evaluated.
Materials and Methods Subjects and Study Design Fourteen women with osteoporosis (forearm fracture following minor trauma) took part in a 5-year study of intranasal calcitonin therapy. In the first 3 years, the women participated in two larger studies [5, 6], carried out using different designs (Table 1). The first, a double-blind study [5] ran for 1 year. In it, eight of the women received sCT (200 IU) intranasally and calcium (500 mg) every day. The other six women received placebo and calcium. No treatment was given in the second year. In the third year, a follow-up study [6] was conducted. An open design was used. All 14 women received 200 IU sCT intranasally and 500 mg calcium each day. The open design study continued for 2 years. Over a period of 5 years, eight women therefore received active treatment for 4 years, six women for 3 years. To allow the optimum interval for therapy to be assessed some data from the first two studies [5, 6] were used in the study reported here.
Measurements of Bone Mass As people live longer, age-related diseases increasingly present problems. Osteoporosis is a major age-related disease affecting millions of people throughout the world, especially women. It is characterized by decreased amount of bone and increased susceptibility to fracture. It is not yet certain whether or not there is any effective treatment once osteoporosis has been diagnosed. Calcitonin is involved in calcium homeostasis. Its main target organ is the skeleton. Calcitonin rapidly inhibits osteoclast activity [ 1] and decreases the plasma concentrations of calcium if bone turnover is high. In the long term, it affects the number of osteoclasts by inhibiting production of osteoclast precursor [2]. Injectable calcitonin has been approved for treatment of osteoporosis in the United States following a controlled trial in which total body calcium was shown to increase significantly in a group receiving salmon calcitonin (sCT) but to fall in a control group [3]. A double-blind study showed that an injection of sCT (100 IU) on alternate days increased forearm bone mineral content [4]. Development of an intranasal dosage form has made long-term therapy more convenient.
Bone mineral content (BMC) of the forearm was measured by single photon absorptiometry (SPA), using a 125I source (3.7 GBq) with a photopeak at 27 KeV. The method determines BMC in the proximal region (BMCarm) as the mean of six scans 4 mm apart just proximal to a site at which the distance between the ulna and the radius is 8 mm. The long-term precision in vivo is 1% [7]. Measurements were performed every 3 months for the first 3 years and every 6 months for the remaining 2 years. The BMC of the lumbar spine (BMCspine) was measured using dual photon absorptiometry (DPA), a DP3 scanner (Lunar Radiation), and a 1530 Gd source (37 GBq) with photopeaks at 44 and 100 KeV. The BMCspi,e was calculated for vertebrae L2 to L4, including intervertebral discs. The long-term precision in vivo for BMCspine is 3.4% after correcting for errors caused by replacement of the source [7, 8]. Measurements were performed once a year for the first 3 years and every 6 months for the last 2 years.
Measurements of Bone Turnover Blood samples were taken and urine was collected in the morning, after overnight fasting and abstinence from tobacco. Serum alkaline
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
$61
Table 1. Study design, clinical data, and initial bone mass measurements (mean • SD) relating to the 14 women who completed the 5-year observation period
Year 1 Year 2 Year 3 Year 4-5
Study design
Number of participants
Placebo-controlled No treatment Open follow-up Open follow-up
17 nasal sCT 17 15 nasal sCT 8 nasal sCT
20 placebo 12 11 nasal sCT 6 nasal sCT
(n = 8)
(n = 6)
Initial data (n = 14) Age (years) Menopausal age (years) Height (cm) Weight (kg) BMCarm (units) BMCspine (g)
phosphatase (sAP) was measured enzymatically according to Scandinavian recommendations [9]. The coefficient of variation was 5%. Plasma bone Gla protein (pBGP) was measured using radioimmunoassay. Intra- and interassay variations were less than 7% and 12% [10]. These results indicate bone formation. Fasting urinary hydroxyproline levels were measured by spectrophotometry [11] and corrected for creatinine excretion (FuHpr/Cr). The intra- and interassay variations were about 10% and 13%. This parameter is an indicator of bone resorption. Measurements were performed every 3 months for the first 3 years and every 6 months for the last 2 years. To eliminate interassay variations of pBGP and FuHpr, samples from each woman were analyzed in the same assays.
Statistical Analysis Pretreatment values were taken to be 100. All subsequent measurements were expressed as percentages of these values, Changes in bone mass with time found through yearly measurements were expressed as percentages of pretreatment values. For measurements performed every 3 and 6 months, average annual changes in bone mass and turnover were calculated on values cumulated since the start of treatment [12]. Changes during the first 2 years were recorded as mean values for each bone compartment in the group receiving 1 year of placebo treatment plus calcium followed by 1 year without treatment. Changes during the 3-year open study were expressed as percentages of the measurements before the period of calcitonin therapy. To allow the optimum therapy interval to be assessed, responses in relation to bone mass and bone turnover were calculated for the various intervals, using values for all participants who had received calcitonin during these intervals. The durations of the intervals were expressed as percentages of the period of observation. The maximum period of treatment was 4 years, since there had been 1 year without treatment. The maximum interval without treatment was 2 years. Changes which would have occurred over a 5-year period were estimated by extrapolation. The significances of differences in changes within groups during the various intervals were tested using Student's t test for paired data.
Results
Table 1 shows the numbers of participants completing the various treatment periods during the observation period. Table 1 also shows clinical data relating to the 14 women studied for the full 5 years and baseline values for BMC measurements. The two groups were well matched. Figure 1 shows changes in BMCspine over 5 years. At the
65.6 • 6.6 19.0 • 160.9 70.4 • 28.2 • 35.3 •
7.3 4.5 8.2 3.3 5.6
59.7 • 2.9 12.3 162.6 73.4 31.2 37.3
• 6.4 --- 5.6 • 15.8 • 4.3 --- 4.5
end of the first 2 years, the group receiving placebo for 1 year had experienced a bone loss of 6.4%, significantly different from the response in the group receiving calcitonin for 1 year (P < 0.01). The same pattern was seen in relation to BMCar m. In the 14 women who completed another 3 years on calcitonin therapy, the BMCspi,e showed an increase after 1 year, which persisted throughout the observation period. Calcitonin administration prevented further declines in BMCar m during the first year, after which the response levelled off. Figure 2 shows responses of BMCspln ~ and BMC~m to different periods of calcitonin therapy. Treatment for about 2 years prevented bone loss in both compartments. A net gain in BMCspin e was attained by extending treatment to 3 years. No further benefit was seen in relation to BMC~rm. Figure 3 shows the effects of various periods of calcitonin therapy on biochemical indicators of bone turnover. The decline in sAP was independent of the duration of treatment. The same pattern was seen for pBGP and FuHpr/Cr.
Discussion
Estrogen replacement is considered to be specific therapy for accelerated bone loss after the menopause [13] and can be instituted at any time after the menopause. If therapy is started early enough, it will prevent fractures of the hip, spine, and distal forearm. Since many women find it inconvenient to start estrogen therapy some years after the menopause, calcitonin administration is an alternative treatment for osteoporosis. The women in the study reported here exhibited moderate degrees of osteoporosis, with average bone losses of 25% to 30% as compared with premenopausal values. They were selected at random from a representative sample and were well matched as regards initial parameters. The study shows that intranasal administration of calcitonin prevented bone loss in women with osteoporosis and that long-term therapy was especially effective in relation to the spine. The effect of calcitonin administration on calcium metabolism has been reported to reach a plateau and even to cease [3]. The exact mechanisms of these phenomena have not yet been clarified, but receptor down-regulation and formation of antibodies have been suggested [14, 15]. In our study, a plateau effect followed by cessation of action was observed in relation to forearms but not to spines. This might indicate that receptors in forearms and spines have different
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
$62 BiCspine
0
-4
-8 I
I
I
I
I
I
0
1
2
,3
4
5
I
1.o traa,m..,I
1F %
o -8
.as., o,,,o,,on,n
Fig. 1. Changes in bone mineral content of the lumbar spine BMCspi,r after different treatment periods. Left: Mean decrease in BMCspine over 2 years after 1 year of placebo therapy. Right: Changes in BMCsp~,e in relation to 3 years of calcitonin therapy.
years
I
~
BMCspine
sAP
%
,T,T
_L
-20
-16
-40 %
Treatment
BMCarm
33
50
67
75
80
1/3
2/4
2/3
3/4
4/5
% years/years
Fig. 3. Response (mean _+ SEM) in terms of serum alkaline phosphatase (sAP) in relation to duration of calcitonin therapy.
~1
-4
uous administration obviously reduces costs of long-term therapy.
-8
0
33
50
67
75
80
%
0/5
1/3
2/4
2/3
3/4
4/5
years/years
Treatment
Fig. 2. Response (mean -+ SEM) in terms of bone mineral content of the lumbar spine (BMCspine)and of the forearm (BMCarm)in relation to duration of calcitonin therapy.
sensitivities to calcitonin, resulting in earlier receptor downregulation in one bone compartment than in the other. This could occur to a greater extent in the forearm because bone turnover there, i.e., the difference between bone formation and bone resorption, is low compared with that in the spine. This supposition is supported by the more prolonged response in the spine and the continuous decline on parameters reflecting bone turnover. Our study indicates that discontinuous intranasal treatment with calcitonin affects bone and calcium metabolism in women with osteoporosis and that the optimum ratio between periods with and without treatment is between 1:2 and 2:3. From the results of the study it is concluded that longterm intranasal treatment with calcitonin is particularly effective in relation to the spine, where a net gain in bone was seen, and that the optimum response in relation to the forearm is achieved using discontinuous therapy. Discontin-
References 1. Singer FR, Melvin KEW, Mills BG (1976) Acute effects of calcitonin on osteoclasts in man. Clin Endocrinol 5:333-340 2. Hedlund T, Hulth A, Johnell O (1983) Early effects ofparathormone and calcitonin on the number of osteoclasts and on serum calcium in rats. Acta Orthop Scand 54:802-804 3. Gruber HE, Ivey JL, Baylink DJ, Matthews M, Nelp WB, Sisom K, Chesnut III CH (1984) Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 33:295-303 4. Mazzuoli GF, Passeri M, Gennari C, Minisola S, Antonelli R, Valtorta C, Palummeri E, Cervellin GF, Gonnelli S, Francini G (1986) Effects of salmon calcitonin in postmenopausal osteoporosis: a controlled double-blind clinical study. Calcif Tissue Int 38:3-8 5. Overgaard K, Riis BJ, Christiansen C, PCdenphant J, Johansen JS (1989) Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 30:435-443 6. Overgaard K, Hansen MA, Nielsen V-AH, Riis BJ, Christiansen C (1990) Discontinuous calcitonin treatment of established osteoporosis---effects of withdrawal of treatment. Am J Med 89:1-6 7. Nilas L, Borg J, Gotfredsen A, Christiansen C (1985) Comparison of single- and dual-photon absorptiometry in postmenopausal bone mineral loss. J Nucl Med 26:1257-1262 8. Nilas L, Hassager C, Christiansen C (1988) Long-term precision
K. Overgaard and C. Christiansen: Long-Term Intranasal Calcitonin
9.
10.
11.
12.
of dual photon absorptiometry in the lumbar spine in clinical settings. Bone Miner 3:305-315 The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology (1974) Recommended methods for the determination of four enzymes in blood. Scand J Clin Lab Invest 33:291-306 Johansen JS, Mr Hansen JE, Christiansen C (1987) A radioimmunoassay for bone Gla protein (BGP) in human plasma. Acta Endocrinol 114:410-416 Pedenphant J, Larsen N-E, Christiansen C (1984) An easy and reliable method for determination of urinary hydroxyproline. Clin Chim Acta 142:145-148 Matthews JNS, Altman DG, Campbell MJ, Royston P (1990)
$63 Analysis of serial measurements in medical research. Br Med J 300:230-235 13. Christiansen C, Christensen MS, McNair P, Hagen C, Stocklund K-E, Transbr I (1980) Prevention of early postmenopausal bone loss: controlled 2-year study in 315 normal females. Eur J Clin Invest 10:273-279 14. Bouizar Z, Rost~ne WH, Milhaud G (1987) Down-regulation of rat kidney calcitonin receptors by salmon calcitonin infusion evidenced by autoradiography. Proc Natl Acad Sci USA 84:5125-5128 15. Levy F, Muff R, Dotti-Sigrist S, Dambacher MA, Fischer JA (1988) Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease. J Clin Endocrinol Metab 67:541-545
