Bone, 12, pp. 311-316 (1991) Printed in the USA. All rights reserved.
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Salmon Calcitonin Treatment by Nasal Spray in Primary Hyperparathyroidism 0. TARRING,
E. BUCHT,
U. SJOSTEDT
and H. E. SJOBERG
Department of Endocrinology, Karolinska Hospital and Institute, Stockholm, Sweden Address for Correspondence and reprints: 0. Tbrring, Sweden.
M.D.,
Ph.D..
Department
of Endocrinology,
Karolinska
Hospital,
S-10401,
Stockholm,
(Malette et al. 1974; Heath et al. 1980; Mundy et al. 1980). Surgical treatment is recommended by most centers, including the Karolinska Hospital (Hodgson et al. 1981; Granberg et al. 1985; Avioli 1986), but the interest in medical therapies has increased during the last decade (Coe 8~ Favus 1980; Posen et al. 1985; Lafferty & Hubay 1989). Even though many patients are relatively asymptomatic and the disease may show few signs of progress (Rao et al. 1988), some patients may deteriorate during a prolonged follow-up (Scholtz et al. 1981), and medical treatment may be necessary in selected cases and where the patient rejects surgical intervention or parathyroidectomy is contraindicated for various reasons. Treatment with oral phosphate (Albright 1932; Broadus et al. 1983), estrogens (Gallagher & Nordin 1972; Selby et al. 1986; Coe et al. 1986). or bisphosphonates (Kaplan et al. 1977; Shane et al. 1981; Douglas et al. 1983) may be considered, but these regiments have gained limited popularity. The calcium-lowering hormone calcitonin (CT) represents a further option, but has previously been considered less favorably because of the need for parenteral administration (Sjoberg & Hjem 1975). However, a formulation of salmon calcitonin (sCT) for convenient intranasal therapy is now available in many countries. Treatment of 1”HPT with i.n. sCT may therefore be an attractive approach, but has not been explored so far. The aim of the present study was to assess the efficacy of different doses of sCT administered by nasal spray to patients with surgically proven 1”HPT. The effect was evaluated by following the ionized calcium concentration in whole blood (B-Ca++ ) during 24 hours after administration of the drug. The levels of plasma sCT were determined using radioimmunoassay.
Abstract The hypocalcemic and hypophosphatemic effect of salmon calcitonin (sCT) given by intranasal (i.n.) spray to 12 patients with histological confirmed primary hyperparathyroidism (1“HPT) was studied. The concentration of ionized calcium in whole blood (B-Ca’+), serum phosphate (S-P), magnesium (S-Mg), plasma sCT (PI-sCT), and endogenous CT (hCT) was followed during five 24-hour periods with at least three days between. After period I (control day), 100 IU sCT was given intramuscularly (i.m.) in period II. In periods III-V, either 110, 200, or 400 IU of sCT were given intranasally (i.n.) in randomized order. Although B-Ca++ decreased from the baseline value with all four sCT treatments and at 4.5 hour on the control day @ < 0.05-0.001), the i.n. sCT treatments had no significant hypocalcemic effect, as the change of the area under the B-Cat+ curve (AAUC B-Ca++) for the three i.n. treatments was not significantly different from the control period @ < 0.001, ANOVA). Only the i.m. injection of calcitonin had a calcium-lowering effect @ < 0.001, ANOVA). Three subjects were considered nonresponders with a decrease in B-Ca” less than 0.06 mmoi/L. S-P decreased within three hours after 200 IU sCT i.n. and 100 IU i.m., but the S-Mg levels showed no consistent changes. The area under the curve for the PI-sCT levels did not correlate with AAUC B-Ca++ except for i.m. given sCT. The endogenous hCT levels were undetectable in almost all patients despite a sensitive RIA for hCT, and did not increase during sCT treatment. Plasma levels of “intact” PTH-(l-&l) increased significantly after 400 IU sCT i.n. at 3 and 6 hours. The local tolerance for the i.n. spray was good and no adverse effects were seen. In conclusion, intranasal sCT treatment (110, 200, or 400 IU) had no significant hypocalcemic effect on B-Ca”. However, S-P decreased after 200 IU i.n. and the PTH levels increased after 400 IU i.n., indicating some biologic effects of i.n. sCT in 1”HPT patients.
Subjects and Methods Subjects
Twelve females, 41-74 years old (63 ‘- 11, mean S SD, median = 65), and one 70-year-old male participated in the study. Only hypercalcemic patients waiting for neck exploration for 1”HPT and who had not been previously treated for hypercalcemia were included. The following exclusion criteria were used: (a) hypercalcemia of origin other than 1”HPT or severe hypercalcemia with a risk for hypercalcemic crisis; (b) patients having vasomotor or allergic rhinitis, uncontrolled cardiac disorders, impaired hepatic or renal function, symptoms of acute or chronic sinusitis, or acute infections of the upper respiratory tract; (c) patients
Key Words: Salmon calcitonin-Intranasal-IntramuscularIonized calcium-Primary hyperparathyroidismHuman calcitonin-Magnesium-Phosphorus-Parathyroid hormone.
Introduction Hypercalcemia due to primary hyperparathyroidism (1”HPT) is an increasingly common finding, especially in elderly patients 311
0. Tarring et al.: Intranasal sCT treatment of 1”HPT
312
Table I. Clinical data for the patients in the study Sex
Age (yr)
Serum calcium (mmol/L)
F F F F F F F F M F F F n = 12
54 73 41 55 64 66 69 70 70 64 71 57 63 ? 9
3.32 2.82 2.72 2.69 2.17 2.85 2.88 2.80 2.87 2.76 2.80 2.86 2.85 lr 0.15
-
Ionized calcium (mmol/L)
Parathyroid histology
1.60 I .49 I .33 1.36 I .38 1.49 I .32 1.32 1.43 1.36
Adenoma -
1.32
Hyperplasia
1.34 1.40 i 0.09
Mean ? SE.
with any concomitant medications known to influence serum calcium levels. One patient, the first to enter the trial, developed frequent vomiting and diarrhea, and fainted after receiving 100 IU i.m. However, she had previously experienced similar symptoms without connection with sCT treatment. As a precaution she was excluded from the study and represents the only dropout from the study. All subjects had normal renal function and all except three were out-clinic patients. Their hypercalcemia was mild to moderate, B-Ca” ranging from 1.32 to 1.60 mmol/L (reference range: 1.14-l .32 mmol/L), and total serum calcium between 2.69 to 3.32 mmol/L (reference range 2.202.60 mmol/L) (Table I). After terminating the study, the diagnosis of 1”HPT was confirmed histologically in all twelve patients by neck-exploration (Table I). Study design The study was carried out over five 24-hour periods with an interval of at least three days between each. Period I was a control day and period II a reference-dose day (100 IU i.m. in the M. Gluteus region). Periods III, IV, and V were treatment days. On each of these, either 110 IU, 200 IU, or 400 IU of sCT (Sandoz, Basel) was administered double-blind intranasally (in.). The sequence in which each patient received the different i.n. doses was randomized. The nasal spray was given at 8 a.m. as one puff of half the total dose in each nostril, and the patient remained at the Calcium Metabolic Unit at the Karolinska Hospital during the following 24 hours. The patients rested supine for the first 4-6 hours and were then allowed to be ambulant as they wished. During the first 5 hours after spraying, 0.5 ml blood was drawn every half hour from a cubital vein for determination of B-Cat+ (Tarring & Sjoberg 1983). B-Ca+’ was then measured at 6. 8. 12, and 24 h. Blood samples for
Table
determination of serum phosphate (S-P), serum magnesium (S-Mg), and endogenous plasma CT (hCT) were taken from the same i.v. cannula at 0, 3, 6, and 24 h, and for plasma sCT at 0, 15 min, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h. To secure adequate hydration of the patient, 100 ml of water or orange juice was served every hour during the fist four hours. A standard, light, low-fat diet was given at 8 a.m., noon, and 4:30-5 p.m.
Methods + was determined with a Ca++ sensitive electrode (ICA lR, Radiometer, Copenhagen), our reference range being 1.141.32 mmol/L (n = 44) (Toning 1985). Serum phosphate (referencerangeO.61.6 mmol/L) andmagnesium (0.65-I .OOmmol/L) were measured by conventional methods. Plasma levels of the endogenous CT levels were measured by a sensitive RIA, as earlier described in detail (Bucht et al. 1985). The detection limit is 8 pg/mL and reference values for women are 11 C 4 pg/mL (n = 40, mean 2 SD). The assay has no cross-reactivity with synthetic sCT (l-32). Plasma parathyroid hormone (FTH) was measured in samples taken during the 400 IU in. period by means of a commercial kit for “intact” human PTH l-84 (Nichols Institute, CA), reference range 12-55 pg/L. Plasma levels of sCT were determined using a sensitive and specific radioimmunoassay with a polyclonal antiserum for salmon calcitonin developed in sheep. The specificity was tested against purified fragments of the peptide and against human calcitonin. Negligible interaction was found over the range of the standard curve. The within- and between-assay variability was 7.5% and 17.5% respectively. The detection limit was 0.026 IU/L, and values below this limit were taken as zero. Analysis of unknown samples used 0.2 ml plasma. B-Ca’
II. Salmon calcitonin (sCT) treatment of primary hypeqxrathyroidism. The change from baseline level of the area under the B-Ca++ curve (cf. Fig. 1) (AAUC B-Ca++. mmol X h X L- ‘) and the total area under the sCT curve (0 to 24 h) (AUC sCT, IU X h X L-‘) during intramuscular (i.m.) or intranasal (i.n.) spray treatment Control
uAUC B-Ca++ AUC sCT
-0.21
2 0.19
100 IU i.m.
- 1.53 ? 0.27” 2.42 2 0.47
110 IU i.n.
200 IU i.n.
-0.49 2 0.19 4.52 r 1.41
-0.34 ? 0.27 5.68 * 1.50
‘p < 0.001 compared with control period; “p < 0.001 compared with the i.m. period; mean 5 SE.
400 IU i.n. -0.78 + 0.14 11.6 + 2.34b
0. Toning et al.: Intranasal sCT treatment of 1”HPT
313
1.45,
)!b&!-p \
1:::
100IUim
. ..**.* l*;:::::::
1.30.
. :
,*
T :
: .
l
0-u
0
1 2
I 4
I 6
I 8
1 24
12
Lu
,i’ 0
1
2
4
6
8
hours
12
24
hours
1.45 Control
l
1.
0~~ / 0
I
2
I
4
I
6
_
l
1
7
1
8
12
0
24
2
4
6
6
12
24
hours
hours
Fig. 1. The concentration
of ionized calcium in whole blood (B-Ca ++) following 100 IU salmon calcitonin (sCT) i.m. (upper left), 110 IU sCT intranasally (i.n.) by spray (upper right), 200 IU sCT in. (lower left), 400 IU sCT in. (lower right), compared with the placebo period. The drug was given at 8:00 a.m. to 12 patients with primary hyperparathyroidism. Mean k SD; *p 0.05; **p < 0.01; ***p < 0.001, compared with baseline values by students paired r-test.
Statistics Two-tailed analysis of variance (ANOVA) followed by Dunnett’s multiple comparison of treatments against a single control group and by Neuman-Keuls multiple comparison of all five groups were performed on the change from baseline level of the area under the B-Ca++ curve (0 to 24 h) (AAUC B-Ca++, mmol x h X L- ‘) and on the total area under the sCT curve (0 to 24 h) (AUC sCT, IU X h X L-r). Student’s paired t-test (two-tailed) was used for analyzing the B-Cal’ changes com-
t 02468
12
24
hours
Fig. 2. The concentration
of sCT in plasma during 24 hours following 100 IU sCT i.m., 110, 200, or 400 IU administered by intranasal spray at 0 hour. Mean 2 SEM.
pared with baseline values during each treatment (Fig. l), and the Wilcoxon nonparametric test for the changes in endogenous CT and PTH levels.
Results Only the i.m. injection of calcitonin caused a significant lowering of B-Caft, as the change of the area under the B-Ca” curve (AAUC B-Cal+) was significantly larger compared with the control period and the three nasal treatment periods (p < 0.001, ANOVA, Table II). Therefore, although B-Cat+ decreased from baseline values with all four sCT treatments and at 4.5 hour on the control day (p < 0.05-0.001, Fig. 1), the results clearly indicate that intranasal sCT has no hypocalcemic effect in l”HpT patients. In three patients (except one where B-Ca’+ decreased 0.09 mmol/L after 200 IU in.) the decrease in B-Ca’+ after any of the four sCT therapies was 5 0.06 mmol/L. These three were considered nonresponders. The AUC sCT increased with the sCT dose; but only the 400 IU i.n. was significantly larger than the three other sCT treatments (Table II). There was no correlation between the AUC sCT and the AAUC B-Ca++ levels, except for the 100 IU i.m. treatment 0, < 0.02, ANOVA). The plasma levels of sCT showed a similar pattern for the i.n. treatments, with an initial rapid absorption phase followed by a slower phase. The inter-individual variations in the plasma sCT levels were, however, greater after in. than after i.m. administration (Fig. 2). Some of the i.n.
0. Toning et al.: Intranasal sCT treatment of 1”HPT
314
Table III. S-Phosphate
Control
Hours PHOSPHATE 0 6 24 MAGNESIUM 0 6 24 Compared Compared
and S-Magnesium
0.83 0.77 0.86 0.84
4 ‘_ + k
0.05 0.04 0.04d 0.05
0.91 2 0.02 0.90 + 0.01 0.90 ? 0.02 0.89 i- 0.02
levels during sCT Treatment 100 IU i.m.
of l”HP7
110 IU i.n.
200 IU i.n.
400 IU i.n.
0.82 0.71 0.80 0.68
2 i 2 k
0.05 0.04” 0.03’ 0.03h
0.82 0.81 0.88 0.83
2 2 2 t
0.06 0.05 0.04 0.04
0.88 + 0.04 0.81 + 0.04” 0.88 rt_ 0.04” 0.83 + 0.03
0.79 0.78 0.87 0.85
t + 2 2
0.92 0.90 0.91 0.91
I c ? t
0.02 0.02 0.02 0.02
0.87 t 0.89 -t 0.88 t 0.86 t
0.02 0.02 0.02 0.02
0.84 0.88 0.87 0.87
0.90 0.91 0.91 0.88
r 0.02 I?I 0.02 2 0.01 f 0.02
r -c t -+
0.02 0.02 0.02 0.02
0.03 0.05 0.04‘ 0.04
to baseline:” = p < 0.05; h = p < 0.01. n = 12. mean -t SE. mmol/L to 3 hour:’ = p < 0.05: ’ = p c 0.01.
treatments caused a sustained elevation of sCT in plasma measurable 24 hours after administration of the drug. None of the patients had detectable sCT in plasma at basal state at all four drug periods. The S-P concentrations decreased significantly after 3 hours both after 100 IU i.m. and after 200 IU i .n. (Table III). From the minimum value at 3 hours. which occurred at 11 a.m., the S-P levels increased both in the control period and in all three i.n. sCT study periods. The S-Mg showed no consistent response to treatment with sCT (Table III). The plasma levels of endogenous CT (hCT) were undetectable in 90% of all samples, and did not increase during any of the five periods. The median and the maximum value (in parentheses) for the group of the plasma hCT at 0. 3, 6, and 24 h are as follows (pg/mL, nd = nondetectable). Control period: nd (14), nd (13), nd (12) and nd; 100 i.m.: nd (9). nd (12), nd and nd (10); 110 i.n.: nd, nd, nd and nd; 200 i.n.: nd. nd, nd and nd (18); and 400 i.n.: nd (lo), nd, nd, nd (8). The plasma PTH value at basal state was elevated, 74 2 31 pmol/mL. mean t SD) and increased significantly after 400 IU was given i.n. to 87 -t 38 after 3 h f$ < 0.01) and 92 2 35 after 6 h @ < 0.01). At 24 h the PI-PTH levels had returned to baseline, 76 + 34 pmol/mL. PI-PTH levels were not available from the other study periods. No significant adverse reactions or local side effects were noted in response to the nasal sCT spray therapy.
Discussion The hypocalcemic effect of three different doses of sCT administered to patients with surgically proven I”HPT was tested in the present study. Analysis of variance showed no significant effect of nasal sCT therapy on the B-Cat+ levels compared with the drug-free control period. A significant decrease in change in area under the curve of the blood concentration of ionized calcium (AAUC B-Ca”) was seen only after intramuscular administration. There may be several reasons why intranasal sCT therapy has insufficient effect in 1”HPT. Although i.n. sCT, in doses comparable to those of the present study, is effective in other disease states of elevated bone turnover, such as Paget’s disease (Reginster et al. 1985), we saw little effect, even though 1”HPT patients have increased bone turnover, as indicated by calcium kinetic data (Charles et al. 1986) and increased activation of new bone remodeling cycles, compared to age and sex-matched controls (Eriksen et al. 1986). Furthermore. Thamsborg et al. (1990) recently showed 50. 100, or 200 IU sCT i.n.. from the same manufacturer as in the present study, to be without effect on the ionized calcium levels in healthy, postmenopausal women
of similar age as in the present study. As the endogenous PTH levels are elevated in postmenopausal women and in l”HPT, as the present study also demonstrates, the absent calcium lowering effect of i.n. sCT in I”HPT and postmenopausal women may be linked to changed responsiveness of the target cells secondary to elevated endogenous PTH levels. An age-related decrease in tissue sensitivity to sCT, however, could be an additional explanation. Doses and i.n. formulations of sCT from the same manufacturer as used in the present study, administered to young, healthy subjects, decrease serum calcium (Kurose et al. 1987 (uncontrolled study); Buclin et al. 1987). S-P, the urinary excretion of phosphate, sodium, chloride, and hydroxyproline also changed one to two hours after i.n. sCT, indicating a clear pharmacologic effect of the drug (Buclin et al. 1987; Nagant de Deuxchaisnes et al. 1987). At present it is uncertain whether the differences in response between young normal subjects and postmenopausal women or patients with 1”HPT is linked to absolute or relative increased endogenous PfH levels or agedependent factors unrelated to PTH. Although 100 IU given i.m. caused significant hypocalcemia and hypophosphatemia and the AAUC B-Ca++ was correlated to the AUC sCT, an equivalent or higher dose i.n. had no demonstrable effect. The shape of the CT signal, the pl-CT curve. which reflects absorption, distribution, and elimination of sCT, therefore may be important for the physiological actions of the peptide. A rapid increase to high plasma concentrations of sCT and a relatively rapid decline to low levels (T,,a approximately 2 h. Fig. 2) may rapidly turn off the increased renal tubular calcium reabsorption and increased bone resorption caused by endogenous elevated PTH, thereby causing the hypocalcemic effects of CT, well known from the clinical situation. When sCT is given i.n. the shape of the sCT curve is different: The rapid increase is followed by a moderate and sustained elevation of plasma sCT levels (Fig. 2). It is conceivable that the sustained elevated sCT levels may cause a “downregulation” of the CT receptors on the renal and skeletal target cellh. as earlier described in I”HPT patients (Sorensen B Hindberg 1970). and thus diminish the hypocalcemic effect of CT. In addition, the sCT induced PI-PTH increase, which is notable as little as three hours after 400 IU sCT i.n., may increase the renal tubular calcium reabsorption and stimulate the bone resorption again, thereby counteracting the hypocalcemic effect of i.n. CT. Observations of the renal response to the different treatments, or of the PTH levels after i.m. administration. were unfortunately not available in the present study. Some plasma samples contained measurable levels at 24 hours after i.n. sCT was given (Fig. 2). Can differences in the result from i.m. versus i.n. administration be explained by a
0. TBrring et al.: Intranasal sCT treatment of 1”HPT
“secondary resistance” or sustained CT-receptor “down-regulation” caused by sCT remaining in the body from previous treatment periods? None of the patients had detectable sCT in plasma at basal state before i.n. sCT was given at any of the three i.n. administration periods; the study was designed to allow a “wash-out” period of at least three days between each i.n. sCT administration, and the order in which the i.n. doses were given were randomized. Nevertheless, the only way to address this issue directly, would be to randomize the order in which all sCT treatments had been given, including the i.m. iniection. The plasma curves for the i.n. administered sCT consist of two phases, an initial rapid increase followed by lower but sustained levels. The first part of the curve may reflect transmucous sCT absorption to the vascular bed, and the second part of the curve, a much slower absorption/distribution through the lymphatic network, as small lymphatic vessels are abundant in the nasal mucosa. However, the plasma sCT data should be interpreted with some caution, as they may indicate about 50% absorption of the drug from the i.n. spray. The possibility of artifactual interference of the RIA for sCT (immunoreactive fragments or metabolites without bioactivity) should be kept in mind. The initial decline in the S-P levels, statistically significant after both i.m. treatment and 200 IU in. spray, is consistent with an acute and transient hypophosphatemic effect of exogenous sCT due to a phosphaturic and anti-resorptive action on bone, as it has been shown in rats (Maier 1977). Three of the patients showed limited responses of the serum electrolytes to i.m. and i.n. administered sCT. Primary resistance to calcitonin treatment has been described also in Paget’s disease (Hamilton 1974), and has always been a problem in calcitonin treatment of hypercalcemia. An explanation for this phenomenon is still lacking, but could be related to the discussion above. The suppression of the endogenous CT levels we found is consistent with previous observations in 1”HPT patients (Tarring et al. 1985; Tiegs et al. 1986). In conclusion, 110, 200, and 400 IU sCT i.n. treatment of hypercalcemia due to 1”HPT did not decrease the B-Cat+ levels compared to a drug-free control period. With 200 IU i.n., however, the phosphorus levels decreased significantly. Overall, intramuscular sCT treatment with 100 IU was more potent and induced more reproducible plasma sCT levels than i.n. treatment. As 1”HPT is diagnosed with increasing frequency, more patients need temporary or permanent medical treatment for hypercalcemia. Although the i.n. spray principle is promising for treatment of osteoporosis and Paget’s disease, it was not effective in decreasing the ionized calcium levels in patients with 1”HPT in the doses used in the present study.
We wish to thank Mrs. Barbro Granberg for skillful technical assistance, Dr. Magnus Axelson, Clinical Chemistry, Karolinska Hospital for determination of Pl-PTH. The study was supported by the Swedish Medical Research Council (grant no. 05992 and B89-19F8567.01) and The Femstrijms Foundation.
Acknowledgemenrs:
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Bucht, E.; Toning. 0.; Sjbberg, H. E. Gel chromatography of imnnmoextracted plasma calcitonin in response to the calcium clamp in healthy males. Acta Endorrinol. (Copeab) 110~423~28; 1985. Buclin, T.; Randin, J. P.; Jacquet, A. F.; Azria, M.; Attinger. M.; Gomez, F.: Burckhardt. P. The effect of rectal and nasal administration of salmon calcitonin in normal subjects. C&if. Tissue Int. 41:252-258; 1987. Charles, P.; Mosekilde, L.; Taagehflj Jensen, F. Primary hyperparathyroidism: evaluated by 47 calcium kinetics, calcium balance and serum bone-Glaprotein. Eur. J. C/in. Invesr. 16:277-283; 1986. Coe, F. L.; Favus, M. I. Does mild, asymptomatic hyperparathyroidism require surgery? N. Engl. J. Med. 302:224225; 1980. Coe, F. L.; Favus, M. J.; Parks, J. H. Is estrogen preferable to surgery for postmenopausal women with primary hyperparathyroidism? N. Engl. J. Med. 314:1508-1509; 1986. Douglas, D. L.; Kanis, J. A.: Paterson, A. D.; Beard, D. J.; Cameron, E. C.; Watson, M. E.: Woodhead, S.; Williams, J.: Russell, R. G. G. Drug treatment of primary hyperparathyroidism. Use of clodronate disodium. Br. Med. .i. 286~587-590: 1983. Eriksen, E. F.; Mosekilde, L.; M&en, F. Trabecular bone remodeling and balance in primary hyperparathyroidism. Bone 7:213-221; 1986. Gallgaher, J. C.: Nordin, B. E. C. Treatment with oestmgens of primary hyperparathyroidism in postmenopausal women. Lancet 1:503-507: 1972. Granberg, P. 0. Cedermark, B.; Fameba, L.-O.: Hamberger, B.; Werner, S. Pamthyroid tumors. Cur. Pro&l. Cancer IX: 11, 1985. Hamilton, C. R. Jr. Effects of synthetic salmon calcitonin in patients with Paget’s disease of bone. Am. J. Med. 56~315-322: 1974. Heath 111, H.; Hodgson, S. F.; Kennedy, M. A. Primary hypxparathyroidism: Incidence. morbidity, and potential economic impact in a community. N. Engl. J. Mqd. 302:189-193; 1980. Hodgson, S. F.: Heath III, H. Asymptomatic primary hyperparathyroidism. Treat or follow? Mayo Clin. Proc. 56521-523: 1981. Kaplan, R. A.: Geho. W. B.; Poindexter, C.; Haussler, M.: Dietz, G. W.; Pak, C. Y. C. Metabolic effects of disphosphonate in primary hyperparathyroidism. 1. C/in. Pharmocol. 17:410419; 1977. Kurose, H.: Seine, Y.; ShimaKurose, H.; Seine, Y.: Shima, M.; Tanaka, H.; lshida. M.: Yamaoka, K.; Yabuuchi, H. lntranasal absorption of salmon calcitonin. C&if. Tissue Inr. 41:249-251; 1987. Lafferty, F. W.; Hubay. C. A. Primary hyperparathyroidism. A review of the long-term surgical and nonsurgical morbidities as a basis for a rational approach to treatment. Arch. Intern. Med. 149:789-796; 1989. Maier, R. Pharmacology of human calcitonin. Maclntyre. I., ed. Human calcitonin and Paget’s disease. Proc. Inr. Workshop, London, 1976. Bern: Huber; 1977166-77. Mallette, L. E.: Bilezikian, J. P.: Heath, D. A.; Aurbach, G. D. Primary hyperparathyroidism: Clinical and biochemical features. Medicine 53: 127146; 1974. Mundy. G. R.; Cove, D. H.: Fisken, R. Primary hyperparathyroidism: Changes in the pattern of clinical presentation. Lancet 1:1317-1320: 1980. Nagant de Deuxchaisnes, C.; Devogelaer, 1. P.: Huaux, J. P.; Dufour, I. P.; Esselinckx, W.; Engelbeen, I. P.; Stasse, P.; Hermans, P.: DeBuisseret, J. P. New modes of administration of salmon calcitonin in Paget’s disease. Nasal spray and suppository. Clin. Orrhoped. Res. 217:5&71: 1987. Pose”, S.; Clifton-Bligh, P.; Reeve, T. S.; Wagstaffe. C.; Wilkinson, M. Is parathyroidectomy of benefit in primary hyperparathyroidism? Q. J. Med. 54:241-251; 1985. Perry, H. M.; Province, M. A.; Drake, D. M.: Kim. G. S.; Shaheb, S.; Avioli, L. V. Diurnal variation of serum calcium and phosphororus in postmenopausal women. C&if. Tissue Im. 38:115-118; 1986. Rae, D. S.: Wilson. R. J.; Kleerekoper. M.; Parfitt, A. M. Lack of biochemical progression or continuation of accelerated bane loss in mild asymptomatic primary hyperparathyroidism: Evidence for biphasic disease course. J. Clin. Endocrinol. Merab. 67~1294-1298; 1988. Reginster. J. Y.; Albert, A.; Franchimont, P. Salmon-calcitonin nasal spray in Paget’s disease of bone: Preliminary results in five patients. Calcify Tissue hr. 37:577-580: 1985. Scholz. D. A.; Pumell, D. C. Asymptomatic primary hyperparathyroidism. IO-year prospective study. Mayo C/in. Proc. 56~473478; 1981. Shane, E.: Baquiran. D. C.; Bilizikian, J. P. Effects of dichloromethylene disphosphonates on semm and urinary calcium in primary hyperparathyroidism. Ann. Intern. Med. 95~23-27; 1981. Selby, P. L.: Peakock, M. Ethinyl estradiol and norethindrone in the treatment of primary hyperparathyroidism in postmenopausal women. N. Engl. J. Med. 314:1481-1485; 1986. Sjdberg. H. E.: Hjem, B. Calcitonin treatment in primary hyperparathyroidism
316
and severe hypercalcemia of other origin. Acta Chir. Stand. 141:90-95; 1915. Sorensen, 0. H.; Hindberg, I. Calcitonin and bone. Lancer 1:1061: 1970. Tiegs, R. D.: Body, J. J.: Barta. J. M.: Heath, H. III. Secretion and metabohsm of monomeric human calcitonin: Effects of age. sex. and thyroid damage. J. Bone Min. Res. 1:339-349; 1986. Thamsborg. G.; Storm, T. L.: Brinch. E.: Sykulski, R.; Fogh-Andersen, N.: Holmegaard, S. N.; Wensen, 0. H. The effect of different doses of nasal salmon calcitonin on plasma cyclic AMP and sawn ionized calcium. C&if. Tissue Int. 46:5-B; 1990 Tfining. 0.: Sjbberg. H. E. A calcium clamp technique in man. Arm Physiol.
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T@ning. 0. Calcitonin response to calcium clamp. Karolinska Institute. holm, Thesis. p. 15; 1985.
Stock-
T@rring. 0.: Bucht. E.; Sjiiberg, H. E. Decreased plasma calcitonin response to a calcium clamp in primary hyperparathyroidism. Acta Endocriml. (Copah). 108:372-376; 1985. Date Received: February 13, 1990 Dare Revised: January 29. 1991 Dare Accepted: February 6, 1991
Copyright
8756-3282/91 $3.00 + .oO 0 1991 Pergamon Press plc
Salmon Calcitonin Treatment by Nasal Spray in Primary Hyperparathyroidism 0. TARRING,
E. BUCHT,
U. SJOSTEDT
and H. E. SJOBERG
Department of Endocrinology, Karolinska Hospital and Institute, Stockholm, Sweden Address for Correspondence and reprints: 0. Tbrring, Sweden.
M.D.,
Ph.D..
Department
of Endocrinology,
Karolinska
Hospital,
S-10401,
Stockholm,
(Malette et al. 1974; Heath et al. 1980; Mundy et al. 1980). Surgical treatment is recommended by most centers, including the Karolinska Hospital (Hodgson et al. 1981; Granberg et al. 1985; Avioli 1986), but the interest in medical therapies has increased during the last decade (Coe 8~ Favus 1980; Posen et al. 1985; Lafferty & Hubay 1989). Even though many patients are relatively asymptomatic and the disease may show few signs of progress (Rao et al. 1988), some patients may deteriorate during a prolonged follow-up (Scholtz et al. 1981), and medical treatment may be necessary in selected cases and where the patient rejects surgical intervention or parathyroidectomy is contraindicated for various reasons. Treatment with oral phosphate (Albright 1932; Broadus et al. 1983), estrogens (Gallagher & Nordin 1972; Selby et al. 1986; Coe et al. 1986). or bisphosphonates (Kaplan et al. 1977; Shane et al. 1981; Douglas et al. 1983) may be considered, but these regiments have gained limited popularity. The calcium-lowering hormone calcitonin (CT) represents a further option, but has previously been considered less favorably because of the need for parenteral administration (Sjoberg & Hjem 1975). However, a formulation of salmon calcitonin (sCT) for convenient intranasal therapy is now available in many countries. Treatment of 1”HPT with i.n. sCT may therefore be an attractive approach, but has not been explored so far. The aim of the present study was to assess the efficacy of different doses of sCT administered by nasal spray to patients with surgically proven 1”HPT. The effect was evaluated by following the ionized calcium concentration in whole blood (B-Ca++ ) during 24 hours after administration of the drug. The levels of plasma sCT were determined using radioimmunoassay.
Abstract The hypocalcemic and hypophosphatemic effect of salmon calcitonin (sCT) given by intranasal (i.n.) spray to 12 patients with histological confirmed primary hyperparathyroidism (1“HPT) was studied. The concentration of ionized calcium in whole blood (B-Ca’+), serum phosphate (S-P), magnesium (S-Mg), plasma sCT (PI-sCT), and endogenous CT (hCT) was followed during five 24-hour periods with at least three days between. After period I (control day), 100 IU sCT was given intramuscularly (i.m.) in period II. In periods III-V, either 110, 200, or 400 IU of sCT were given intranasally (i.n.) in randomized order. Although B-Ca++ decreased from the baseline value with all four sCT treatments and at 4.5 hour on the control day @ < 0.05-0.001), the i.n. sCT treatments had no significant hypocalcemic effect, as the change of the area under the B-Cat+ curve (AAUC B-Ca++) for the three i.n. treatments was not significantly different from the control period @ < 0.001, ANOVA). Only the i.m. injection of calcitonin had a calcium-lowering effect @ < 0.001, ANOVA). Three subjects were considered nonresponders with a decrease in B-Ca” less than 0.06 mmoi/L. S-P decreased within three hours after 200 IU sCT i.n. and 100 IU i.m., but the S-Mg levels showed no consistent changes. The area under the curve for the PI-sCT levels did not correlate with AAUC B-Ca++ except for i.m. given sCT. The endogenous hCT levels were undetectable in almost all patients despite a sensitive RIA for hCT, and did not increase during sCT treatment. Plasma levels of “intact” PTH-(l-&l) increased significantly after 400 IU sCT i.n. at 3 and 6 hours. The local tolerance for the i.n. spray was good and no adverse effects were seen. In conclusion, intranasal sCT treatment (110, 200, or 400 IU) had no significant hypocalcemic effect on B-Ca”. However, S-P decreased after 200 IU i.n. and the PTH levels increased after 400 IU i.n., indicating some biologic effects of i.n. sCT in 1”HPT patients.
Subjects and Methods Subjects
Twelve females, 41-74 years old (63 ‘- 11, mean S SD, median = 65), and one 70-year-old male participated in the study. Only hypercalcemic patients waiting for neck exploration for 1”HPT and who had not been previously treated for hypercalcemia were included. The following exclusion criteria were used: (a) hypercalcemia of origin other than 1”HPT or severe hypercalcemia with a risk for hypercalcemic crisis; (b) patients having vasomotor or allergic rhinitis, uncontrolled cardiac disorders, impaired hepatic or renal function, symptoms of acute or chronic sinusitis, or acute infections of the upper respiratory tract; (c) patients
Key Words: Salmon calcitonin-Intranasal-IntramuscularIonized calcium-Primary hyperparathyroidismHuman calcitonin-Magnesium-Phosphorus-Parathyroid hormone.
Introduction Hypercalcemia due to primary hyperparathyroidism (1”HPT) is an increasingly common finding, especially in elderly patients 311
0. Tarring et al.: Intranasal sCT treatment of 1”HPT
312
Table I. Clinical data for the patients in the study Sex
Age (yr)
Serum calcium (mmol/L)
F F F F F F F F M F F F n = 12
54 73 41 55 64 66 69 70 70 64 71 57 63 ? 9
3.32 2.82 2.72 2.69 2.17 2.85 2.88 2.80 2.87 2.76 2.80 2.86 2.85 lr 0.15
-
Ionized calcium (mmol/L)
Parathyroid histology
1.60 I .49 I .33 1.36 I .38 1.49 I .32 1.32 1.43 1.36
Adenoma -
1.32
Hyperplasia
1.34 1.40 i 0.09
Mean ? SE.
with any concomitant medications known to influence serum calcium levels. One patient, the first to enter the trial, developed frequent vomiting and diarrhea, and fainted after receiving 100 IU i.m. However, she had previously experienced similar symptoms without connection with sCT treatment. As a precaution she was excluded from the study and represents the only dropout from the study. All subjects had normal renal function and all except three were out-clinic patients. Their hypercalcemia was mild to moderate, B-Ca” ranging from 1.32 to 1.60 mmol/L (reference range: 1.14-l .32 mmol/L), and total serum calcium between 2.69 to 3.32 mmol/L (reference range 2.202.60 mmol/L) (Table I). After terminating the study, the diagnosis of 1”HPT was confirmed histologically in all twelve patients by neck-exploration (Table I). Study design The study was carried out over five 24-hour periods with an interval of at least three days between each. Period I was a control day and period II a reference-dose day (100 IU i.m. in the M. Gluteus region). Periods III, IV, and V were treatment days. On each of these, either 110 IU, 200 IU, or 400 IU of sCT (Sandoz, Basel) was administered double-blind intranasally (in.). The sequence in which each patient received the different i.n. doses was randomized. The nasal spray was given at 8 a.m. as one puff of half the total dose in each nostril, and the patient remained at the Calcium Metabolic Unit at the Karolinska Hospital during the following 24 hours. The patients rested supine for the first 4-6 hours and were then allowed to be ambulant as they wished. During the first 5 hours after spraying, 0.5 ml blood was drawn every half hour from a cubital vein for determination of B-Cat+ (Tarring & Sjoberg 1983). B-Ca+’ was then measured at 6. 8. 12, and 24 h. Blood samples for
Table
determination of serum phosphate (S-P), serum magnesium (S-Mg), and endogenous plasma CT (hCT) were taken from the same i.v. cannula at 0, 3, 6, and 24 h, and for plasma sCT at 0, 15 min, 1, 2, 3, 4, 5, 6, 8, 12, and 24 h. To secure adequate hydration of the patient, 100 ml of water or orange juice was served every hour during the fist four hours. A standard, light, low-fat diet was given at 8 a.m., noon, and 4:30-5 p.m.
Methods + was determined with a Ca++ sensitive electrode (ICA lR, Radiometer, Copenhagen), our reference range being 1.141.32 mmol/L (n = 44) (Toning 1985). Serum phosphate (referencerangeO.61.6 mmol/L) andmagnesium (0.65-I .OOmmol/L) were measured by conventional methods. Plasma levels of the endogenous CT levels were measured by a sensitive RIA, as earlier described in detail (Bucht et al. 1985). The detection limit is 8 pg/mL and reference values for women are 11 C 4 pg/mL (n = 40, mean 2 SD). The assay has no cross-reactivity with synthetic sCT (l-32). Plasma parathyroid hormone (FTH) was measured in samples taken during the 400 IU in. period by means of a commercial kit for “intact” human PTH l-84 (Nichols Institute, CA), reference range 12-55 pg/L. Plasma levels of sCT were determined using a sensitive and specific radioimmunoassay with a polyclonal antiserum for salmon calcitonin developed in sheep. The specificity was tested against purified fragments of the peptide and against human calcitonin. Negligible interaction was found over the range of the standard curve. The within- and between-assay variability was 7.5% and 17.5% respectively. The detection limit was 0.026 IU/L, and values below this limit were taken as zero. Analysis of unknown samples used 0.2 ml plasma. B-Ca’
II. Salmon calcitonin (sCT) treatment of primary hypeqxrathyroidism. The change from baseline level of the area under the B-Ca++ curve (cf. Fig. 1) (AAUC B-Ca++. mmol X h X L- ‘) and the total area under the sCT curve (0 to 24 h) (AUC sCT, IU X h X L-‘) during intramuscular (i.m.) or intranasal (i.n.) spray treatment Control
uAUC B-Ca++ AUC sCT
-0.21
2 0.19
100 IU i.m.
- 1.53 ? 0.27” 2.42 2 0.47
110 IU i.n.
200 IU i.n.
-0.49 2 0.19 4.52 r 1.41
-0.34 ? 0.27 5.68 * 1.50
‘p < 0.001 compared with control period; “p < 0.001 compared with the i.m. period; mean 5 SE.
400 IU i.n. -0.78 + 0.14 11.6 + 2.34b
0. Toning et al.: Intranasal sCT treatment of 1”HPT
313
1.45,
)!b&!-p \
1:::
100IUim
. ..**.* l*;:::::::
1.30.
. :
,*
T :
: .
l
0-u
0
1 2
I 4
I 6
I 8
1 24
12
Lu
,i’ 0
1
2
4
6
8
hours
12
24
hours
1.45 Control
l
1.
0~~ / 0
I
2
I
4
I
6
_
l
1
7
1
8
12
0
24
2
4
6
6
12
24
hours
hours
Fig. 1. The concentration
of ionized calcium in whole blood (B-Ca ++) following 100 IU salmon calcitonin (sCT) i.m. (upper left), 110 IU sCT intranasally (i.n.) by spray (upper right), 200 IU sCT in. (lower left), 400 IU sCT in. (lower right), compared with the placebo period. The drug was given at 8:00 a.m. to 12 patients with primary hyperparathyroidism. Mean k SD; *p 0.05; **p < 0.01; ***p < 0.001, compared with baseline values by students paired r-test.
Statistics Two-tailed analysis of variance (ANOVA) followed by Dunnett’s multiple comparison of treatments against a single control group and by Neuman-Keuls multiple comparison of all five groups were performed on the change from baseline level of the area under the B-Ca++ curve (0 to 24 h) (AAUC B-Ca++, mmol x h X L- ‘) and on the total area under the sCT curve (0 to 24 h) (AUC sCT, IU X h X L-r). Student’s paired t-test (two-tailed) was used for analyzing the B-Cal’ changes com-
t 02468
12
24
hours
Fig. 2. The concentration
of sCT in plasma during 24 hours following 100 IU sCT i.m., 110, 200, or 400 IU administered by intranasal spray at 0 hour. Mean 2 SEM.
pared with baseline values during each treatment (Fig. l), and the Wilcoxon nonparametric test for the changes in endogenous CT and PTH levels.
Results Only the i.m. injection of calcitonin caused a significant lowering of B-Caft, as the change of the area under the B-Ca” curve (AAUC B-Cal+) was significantly larger compared with the control period and the three nasal treatment periods (p < 0.001, ANOVA, Table II). Therefore, although B-Cat+ decreased from baseline values with all four sCT treatments and at 4.5 hour on the control day (p < 0.05-0.001, Fig. 1), the results clearly indicate that intranasal sCT has no hypocalcemic effect in l”HpT patients. In three patients (except one where B-Ca’+ decreased 0.09 mmol/L after 200 IU in.) the decrease in B-Ca’+ after any of the four sCT therapies was 5 0.06 mmol/L. These three were considered nonresponders. The AUC sCT increased with the sCT dose; but only the 400 IU i.n. was significantly larger than the three other sCT treatments (Table II). There was no correlation between the AUC sCT and the AAUC B-Ca++ levels, except for the 100 IU i.m. treatment 0, < 0.02, ANOVA). The plasma levels of sCT showed a similar pattern for the i.n. treatments, with an initial rapid absorption phase followed by a slower phase. The inter-individual variations in the plasma sCT levels were, however, greater after in. than after i.m. administration (Fig. 2). Some of the i.n.
0. Toning et al.: Intranasal sCT treatment of 1”HPT
314
Table III. S-Phosphate
Control
Hours PHOSPHATE 0 6 24 MAGNESIUM 0 6 24 Compared Compared
and S-Magnesium
0.83 0.77 0.86 0.84
4 ‘_ + k
0.05 0.04 0.04d 0.05
0.91 2 0.02 0.90 + 0.01 0.90 ? 0.02 0.89 i- 0.02
levels during sCT Treatment 100 IU i.m.
of l”HP7
110 IU i.n.
200 IU i.n.
400 IU i.n.
0.82 0.71 0.80 0.68
2 i 2 k
0.05 0.04” 0.03’ 0.03h
0.82 0.81 0.88 0.83
2 2 2 t
0.06 0.05 0.04 0.04
0.88 + 0.04 0.81 + 0.04” 0.88 rt_ 0.04” 0.83 + 0.03
0.79 0.78 0.87 0.85
t + 2 2
0.92 0.90 0.91 0.91
I c ? t
0.02 0.02 0.02 0.02
0.87 t 0.89 -t 0.88 t 0.86 t
0.02 0.02 0.02 0.02
0.84 0.88 0.87 0.87
0.90 0.91 0.91 0.88
r 0.02 I?I 0.02 2 0.01 f 0.02
r -c t -+
0.02 0.02 0.02 0.02
0.03 0.05 0.04‘ 0.04
to baseline:” = p < 0.05; h = p < 0.01. n = 12. mean -t SE. mmol/L to 3 hour:’ = p < 0.05: ’ = p c 0.01.
treatments caused a sustained elevation of sCT in plasma measurable 24 hours after administration of the drug. None of the patients had detectable sCT in plasma at basal state at all four drug periods. The S-P concentrations decreased significantly after 3 hours both after 100 IU i.m. and after 200 IU i .n. (Table III). From the minimum value at 3 hours. which occurred at 11 a.m., the S-P levels increased both in the control period and in all three i.n. sCT study periods. The S-Mg showed no consistent response to treatment with sCT (Table III). The plasma levels of endogenous CT (hCT) were undetectable in 90% of all samples, and did not increase during any of the five periods. The median and the maximum value (in parentheses) for the group of the plasma hCT at 0. 3, 6, and 24 h are as follows (pg/mL, nd = nondetectable). Control period: nd (14), nd (13), nd (12) and nd; 100 i.m.: nd (9). nd (12), nd and nd (10); 110 i.n.: nd, nd, nd and nd; 200 i.n.: nd. nd, nd and nd (18); and 400 i.n.: nd (lo), nd, nd, nd (8). The plasma PTH value at basal state was elevated, 74 2 31 pmol/mL. mean t SD) and increased significantly after 400 IU was given i.n. to 87 -t 38 after 3 h f$ < 0.01) and 92 2 35 after 6 h @ < 0.01). At 24 h the PI-PTH levels had returned to baseline, 76 + 34 pmol/mL. PI-PTH levels were not available from the other study periods. No significant adverse reactions or local side effects were noted in response to the nasal sCT spray therapy.
Discussion The hypocalcemic effect of three different doses of sCT administered to patients with surgically proven I”HPT was tested in the present study. Analysis of variance showed no significant effect of nasal sCT therapy on the B-Cat+ levels compared with the drug-free control period. A significant decrease in change in area under the curve of the blood concentration of ionized calcium (AAUC B-Ca”) was seen only after intramuscular administration. There may be several reasons why intranasal sCT therapy has insufficient effect in 1”HPT. Although i.n. sCT, in doses comparable to those of the present study, is effective in other disease states of elevated bone turnover, such as Paget’s disease (Reginster et al. 1985), we saw little effect, even though 1”HPT patients have increased bone turnover, as indicated by calcium kinetic data (Charles et al. 1986) and increased activation of new bone remodeling cycles, compared to age and sex-matched controls (Eriksen et al. 1986). Furthermore. Thamsborg et al. (1990) recently showed 50. 100, or 200 IU sCT i.n.. from the same manufacturer as in the present study, to be without effect on the ionized calcium levels in healthy, postmenopausal women
of similar age as in the present study. As the endogenous PTH levels are elevated in postmenopausal women and in l”HPT, as the present study also demonstrates, the absent calcium lowering effect of i.n. sCT in I”HPT and postmenopausal women may be linked to changed responsiveness of the target cells secondary to elevated endogenous PTH levels. An age-related decrease in tissue sensitivity to sCT, however, could be an additional explanation. Doses and i.n. formulations of sCT from the same manufacturer as used in the present study, administered to young, healthy subjects, decrease serum calcium (Kurose et al. 1987 (uncontrolled study); Buclin et al. 1987). S-P, the urinary excretion of phosphate, sodium, chloride, and hydroxyproline also changed one to two hours after i.n. sCT, indicating a clear pharmacologic effect of the drug (Buclin et al. 1987; Nagant de Deuxchaisnes et al. 1987). At present it is uncertain whether the differences in response between young normal subjects and postmenopausal women or patients with 1”HPT is linked to absolute or relative increased endogenous PfH levels or agedependent factors unrelated to PTH. Although 100 IU given i.m. caused significant hypocalcemia and hypophosphatemia and the AAUC B-Ca++ was correlated to the AUC sCT, an equivalent or higher dose i.n. had no demonstrable effect. The shape of the CT signal, the pl-CT curve. which reflects absorption, distribution, and elimination of sCT, therefore may be important for the physiological actions of the peptide. A rapid increase to high plasma concentrations of sCT and a relatively rapid decline to low levels (T,,a approximately 2 h. Fig. 2) may rapidly turn off the increased renal tubular calcium reabsorption and increased bone resorption caused by endogenous elevated PTH, thereby causing the hypocalcemic effects of CT, well known from the clinical situation. When sCT is given i.n. the shape of the sCT curve is different: The rapid increase is followed by a moderate and sustained elevation of plasma sCT levels (Fig. 2). It is conceivable that the sustained elevated sCT levels may cause a “downregulation” of the CT receptors on the renal and skeletal target cellh. as earlier described in I”HPT patients (Sorensen B Hindberg 1970). and thus diminish the hypocalcemic effect of CT. In addition, the sCT induced PI-PTH increase, which is notable as little as three hours after 400 IU sCT i.n., may increase the renal tubular calcium reabsorption and stimulate the bone resorption again, thereby counteracting the hypocalcemic effect of i.n. CT. Observations of the renal response to the different treatments, or of the PTH levels after i.m. administration. were unfortunately not available in the present study. Some plasma samples contained measurable levels at 24 hours after i.n. sCT was given (Fig. 2). Can differences in the result from i.m. versus i.n. administration be explained by a
0. TBrring et al.: Intranasal sCT treatment of 1”HPT
“secondary resistance” or sustained CT-receptor “down-regulation” caused by sCT remaining in the body from previous treatment periods? None of the patients had detectable sCT in plasma at basal state before i.n. sCT was given at any of the three i.n. administration periods; the study was designed to allow a “wash-out” period of at least three days between each i.n. sCT administration, and the order in which the i.n. doses were given were randomized. Nevertheless, the only way to address this issue directly, would be to randomize the order in which all sCT treatments had been given, including the i.m. iniection. The plasma curves for the i.n. administered sCT consist of two phases, an initial rapid increase followed by lower but sustained levels. The first part of the curve may reflect transmucous sCT absorption to the vascular bed, and the second part of the curve, a much slower absorption/distribution through the lymphatic network, as small lymphatic vessels are abundant in the nasal mucosa. However, the plasma sCT data should be interpreted with some caution, as they may indicate about 50% absorption of the drug from the i.n. spray. The possibility of artifactual interference of the RIA for sCT (immunoreactive fragments or metabolites without bioactivity) should be kept in mind. The initial decline in the S-P levels, statistically significant after both i.m. treatment and 200 IU in. spray, is consistent with an acute and transient hypophosphatemic effect of exogenous sCT due to a phosphaturic and anti-resorptive action on bone, as it has been shown in rats (Maier 1977). Three of the patients showed limited responses of the serum electrolytes to i.m. and i.n. administered sCT. Primary resistance to calcitonin treatment has been described also in Paget’s disease (Hamilton 1974), and has always been a problem in calcitonin treatment of hypercalcemia. An explanation for this phenomenon is still lacking, but could be related to the discussion above. The suppression of the endogenous CT levels we found is consistent with previous observations in 1”HPT patients (Tarring et al. 1985; Tiegs et al. 1986). In conclusion, 110, 200, and 400 IU sCT i.n. treatment of hypercalcemia due to 1”HPT did not decrease the B-Cat+ levels compared to a drug-free control period. With 200 IU i.n., however, the phosphorus levels decreased significantly. Overall, intramuscular sCT treatment with 100 IU was more potent and induced more reproducible plasma sCT levels than i.n. treatment. As 1”HPT is diagnosed with increasing frequency, more patients need temporary or permanent medical treatment for hypercalcemia. Although the i.n. spray principle is promising for treatment of osteoporosis and Paget’s disease, it was not effective in decreasing the ionized calcium levels in patients with 1”HPT in the doses used in the present study.
We wish to thank Mrs. Barbro Granberg for skillful technical assistance, Dr. Magnus Axelson, Clinical Chemistry, Karolinska Hospital for determination of Pl-PTH. The study was supported by the Swedish Medical Research Council (grant no. 05992 and B89-19F8567.01) and The Femstrijms Foundation.
Acknowledgemenrs:
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T@rring. 0.: Bucht. E.; Sjiiberg, H. E. Decreased plasma calcitonin response to a calcium clamp in primary hyperparathyroidism. Acta Endocriml. (Copah). 108:372-376; 1985. Date Received: February 13, 1990 Dare Revised: January 29. 1991 Dare Accepted: February 6, 1991
