Calcif Tissue lnt (1992) 50:7-10
Calcified Tissue International 9 1992 Springer-Veflag New York Inc.
Clinical Investigations Three-Year Calcitonin Combination Therapy for Postmenopausal Osteoporosis with Crush Fractures of the Spine Jfinos Sziics, Csaba Horv~ith, l~va Kollin, Mikl6s Szathmfiri, and Istvfin Holl6 I st
Department of Medicine, Semmelweis University Medical School, Budapest, Korfinyi S. u. 2/a. 1083-Hungary
Received July 7, 1990, and in revised form February 5, 1991
Summary. Forty-five postmenopausal osteoporotic women with at least one osteoporotic vertebral crush fracture were randomized into three treatment groups. Each patient was on calcitonin, 50 U, on alternate days for 2 weeks monthly (350 U/month), and 500 rag/day oral calcium supplementation. In group II, this therapy was supplemented with phosphate (750 mg/day), and in group III, norandrostenolone decanoate (50 mg/month) was added to the calcitonin + calcium therapy. Bone mineral content, by single photon absorptiometry, of the radius midshaft and distal site (3 cm), as well as the lumbar and metacarpal radiomorphometrical indices were estimated semiannually. The therapeutic trial lasted 36 months except in the phosphate supplementation group, where, due to unfavorable results, treatment was discontinued after 24 months. Calcitonin practically prevented further bone loss for 24 months even in this relatively small and intermittent dosage. Phosphate supplementation was without benefit; however, according to the majority of the examined parameters, combination of calcitonin with the anabolic steroid norandrostenolone decanoate extended efficacy up to 36 months. This latter combination seems to be a promising, relatively inexpensive therapeutic regimen in the treatment of established postmenopausal osteoporosis. Key words: Postmenopausal osteoporosis - Small-dose calcitonin - Norandrostenolone decanoate - Intermittent ad-
ministration.
Menopausal osteoporosis is one of the biggest challenges to public health. Early diagnosis is difficult: the new, more sensitive methods (quantitative computed tomography, photon absorptiometry) are expensive and are not available everywhere. Prevention with elevated dietary calcium ingestion and exercise is generally accepted but often not sufficient. Estrogen therapy is primarily preventive and is not without hazards, even in an at-risk population. The therapy for established osteoporosis (i.e., generalized osteoporosis causing crush fractures of the spine) is still under debate. Calcitonin is often used but high costs and diminishing results in the second year of therapy [1] limit its
Offprint requests to: J. Szfics
value. Sodium fluoride stimulates bone formation--mainly at the axial rather than the peripheral skeleton--without decreasing the risk of vertebral crush fractures but increasing the number of nonvertebral fractures [2]; cyclical use of etidronate [3] seems to be a promising but still not widespread method. The aim of our trial was threefold: (1) to elaborate on a relatively inexpensive schedule using calcitonin in small doses, and with periodical administration; (2) to check the efficacy of our schedule over a period of 2-3 years; and (3) to establish if combination with other agents has any benefit on calcitonin monotherapy.
Patients and Methods Treatment was initiated on 45 postmenopausal women (aged 49--69, mean: 59.5 years) with established osteoporosis, i.e., besides osteoporosis, at least one osteoporotic crush fracture of the dorsolumbar spine was present without significant trauma or any other known reason. Detailed clinical examinations excluded hepatic, renal, hematological or malignant diseases, diabetes mellitus, or other endocrine disorders, Hyperparathyroidism was excluded by measuring serum calcium (total and ionized), phosphate, and C-terminal parathormone level and by determining tubular phosphate reabsorption. Normal serum 25-hydroxycholecalciferol levels and normal urinary output of calcium excluded osteomaiacia or hypercalciuric osteopenia. Informed consent was always obtained. Before treatment, a bidirectional X-ray film was taken of the dorsolumbar spine, both hands and femurs, and radiomorphometrical indices according to Barnett and Nordin [4] were calculated. Bone mineral content was measured on the midshaft and distal (3 cm) site of the nondominant radius with a Norland-Cameron 178 single photon densitometer. Results were received as the mean value of five parallel measurements. Long-time precision in our laboratory was 0.9% in phantom experiments [5]. Before therapy, total blood count, urinalysis, ionogramme, serum GOT, gamma GT, alkaline phosphatase, creatinine, total protein and electrophoresis, and postprandial blood glucose were measured by routine methods mainly on a Hitachi auto-analyzer. Serum calcium, phosphorus, and 24-hour urinary output of calcium were measured by atomic absorption spectrophotometry, and ionized calcium was determined with an Orion Space Stat unit. Radioimmunoassay methods were used for hormonal determinations (T-4, PTH, calcitonin, cortisol, 25-hydroxycholecalciferol). To monitor side effects of the treatment, laboratory checkups and clinical examinations were carried out monthly in the first year and bimonthly in the second and third years. Hormonal determinations as well as radiological examinations were done semiannually.
J. Sz~lcs et al.: Three-Year Calcitonin Combination Therapy for Osteoporosis
8
Rodfus midshoft
%
NETACAf?PAL RAD/OMORPHOMETR/CALINDICES" (M I I )
I10 %
100
l
..... ~.......... ~
~ ' ' ~ .......
90.
% 90,
80-
~2
"
80 6
t2
18 24 30 Radius distot (2cm)
36 months
%
6
110]
I2
18
24
30
36
months
LUMBAR B/CONCAVfTY RADfOMORPHOMETR/CALINDICES (L ZIZ) %
100
flO
}', '+' 3 80
lit
100
I~ 90.
6 12 t8 24 30 36 months Fig, 1. Single photon absorptiometry of patients with postmenopausal osteoporosis. Results are expressed as percentage of initial values (mean, standard deviation). Significant change (*P < 0.05; **P < 0.01) from initial values. ( ~ ) C; (--) C + P; ( . . . . . ) C+A.
Statistical analysis included Student's t test within the groups and analysis of variance (ANOVA) between the groups.
Therapy Unrestricted diet was supplemented with Calcium Sandoz tablets 500 mg daily. Each patient was on Miacatcic (Sandoz), 50 U, every other day for 2 weeks per month followed by a 2-week pause (i.e., seven injections = 350 U/month). Patients were randomized into three groups. Patients in group I received ealcitonin only, in group II therapy was supplemented continuously with phosphate (Phosphor Forte, Sandoz, 750 mg/day), and in group III, norandrostenolone decanoate injections (Retabotil, Richter, 50 rag) were administered monthly in addition to calcitonin. Within 2 years, 2 dropouts occurred: 1 from group II after 1 year due to nausea, and 1 from group Ill after 18 months due to a car accident. In the third year, therapy was terminated in the case of" 1 patient in group Ht because of nausea. Three patients each, completely symptom free, from groups I and III asked for discontinuation for nonmedicat reasons. As we planned to treat patients with advanced osteoporosis for 2 or 3 years, the untreated control group was omitted for ethical reasons. Results were evaluated for 43 patients.
Results There was no significant bone loss during the first 2 years of therapy in group I (calcitonin alone) and in group III (calci-
60
6
12
18
24
30
36
months
Fig. 2. Radiomorphometrical indices of patients with postmenopausal osteoporosis. Results are expressed as percentage of initial values (mean, standard deviation). Significant change (*P < 0.05; **p < 0.01) from initial values. (- ) C; (--) C + P; ( . . . . . ) C+A.
tonin + anabolic steroid). The rate of bone loss--if a n y - was very slow compared with what would be expected in this female population. Combination with phosphate was without benefit: a slight decrease was detected, which became statistically significant at months 18 and 24, therefore, this form of combination was discontinued after 24 months. Figures represent results expressed as a percentage of the initial values. A slight decrease was observed for group I (calcitonin only) in the third y e a r b u t c o m b i n a t i o n with n o r a n drostenolone nearly maimained efficacy. Using ANOVA, we could not find any stmistically significant difference among the groups. Taking single photon absorptiometry at the radius midshaft, a significant (t = 3.00, P < 0.05) decrease was already registered for group II at I8 months. I n the two other groups, bone mineral content was almost stable and the decrease was statistically significant only at 36 months (group I: t = 3.67, P < 0.01; group HI: t = 2.74, P < 0.05). On the distal radius, the change was never significant in the case of group III, whereas for group I, the decrease was significant at 36 months (t = 3.44, P < 0.01). By radiomorphometry, the changes in femoral indices were very slight, without significance in all groups (no fig-
J. Szfics et al.: Three-Year Calcitonin Combination Therapy for Osteoporosis ure). During the whole period, metacarpal indices slightly increased in groups I and III but not in group II. Lumbar biconcavity indices decreased in group I from 18 months (t = 2.90, P < 0.05), but in group III, no significant decrease occurred. The analgesic effect of calcitonin was remarkable even after the first week: patients reported diminishing pains, an effect that lasted during the 2-week pause and during the whole trial. During the 1,396 patient-months on therapy, only two new crush fractures occurred: one in the first month of therapy (group III) and one in the 20th month (group II). Patients reported diminishing height (4-14 cm) in the years before therapy. This reduction stopped almost completely during therapy. Treatment for group II was terminated after 2 years because of unfavorable results compared with the other two groups. Side effects were rare and minimal. In some cases, patients reported flushes a few minutes after injections, mainly on the chin and ear, and sometimes mild nausea which disappeared spontaneously. Routine laboratory findings were always within normal limits. No significant changes were o b s e r v e d in serum calcium, p h o s p h a t e , alkaline phosphatase, or parathyroid hormone levels.
Discussion
Previous observations in menopausal women with osteoporosis disclosed decreased reserve capacity [6], biological half-life, or efficacy of calcitonin [7] due to decreased adrenal androgen production. Serum levels of dehydroepiandrosterone sulfate [8] and androstendione [9] were decreased. In animal experiments [10] and in osteoporotic women [11], norandrostenolone decanoate restored calcitonin sensitivity. These observations raised the possibility that combination with norandrostenolone may enhance the antiresorptive effect of calcitonin on the bone. Moreover, the main problems with calcitonin therapy are the high cost of treatment and the inconvenience of injections. To obtain a better cost-benefit ratio and better acceptance we used relatively small doses, and the form of administration was intermittent, requiring seven injections monthly. Our preliminary results [12, 13] suggested some benefit to this combination in the therapy of postmenopausal osteoporosis. It is well known that phosphate may enhance the hypocalcemic effect of calcitonin [14]. There are data on the direct action of phosphate in promoting osteoblast activity and bone formation [15]. A combined phosphate-calcitonin therapy for osteoporosis was suggested previously [16]. As we planned our therapeutic trial for 2-3 years, and omitted a placebo-treated group for ethical reasons, we decided to administer phosphate, which, similar to androgens (anabolics), may also enhance calcitonin effect. Comparing the results of these three forms of therapy (the two combinations and calcitonin monotherapy), we unfortunately found the combination of calcitonin with phosphate in our study to be without benefit. The aim of osteoporosis therapy is to reduce fracture risk. To evaluate the effect of a special therapy from this point of view is difficult [17], because consecutive crush fractures of the spine in a patient often follow years later. However, only two new crush fractures in 1,396 patientmonths suggest at least some effect. This result is even better if we consider that the first crush fracture occurred in the first month of therapy and the other one developed in the phosphate-calcitonin group, which seemed to us to be an
unfavorable combination. In comparing our results with a recent study, the difference is striking: Itoi et al. [18] found a fracture rate of 41/100 patient years in osteoporotic women on 1 alfa hydroxyvitamin D3, whereas we found only 2/116 patient years. In the study of Watts et al. [3], the vertebral fracture rate was approximately 13/100 patient years in the placebo-treated group and 4.2/100 in those who were on etidronate. The analgesic effect of calcitonin was noteworthy: we think that this was one of the most important reasons why patients liked this form of therapy. Perhaps it is an explanation for the good compliance or for the few dropouts. Results obtained in this 36-month study strongly suggest that calcitonin, even in small doses, is a safe and effective antiresorptive therapeutic agent, at least for 2 years. In the calcitonin only and in the calcitonin + anabolic groups, of the five radiological parameters (two single photon absorptiometry, three radiomorphometry), only the lumbar biconcavity index decreased significantly in the calcitonin only group; the others did not. Combination with an anabolic steroid, norandrostenolone was again without side effects and extended efficacy for up to 3 years. Bone mineral content did not increase but the decrease was very slow, the pains of the patients diminished, and new crush fractures or other fractures did not occur. At the end of this 3-year study, the metacarpal and femoral radiomorphometrical indices did not change significantly: this was the case in the calcitonin + anabolic group with the single photon absorptiometry of the distal radius. A small but significant decrease occurred at the radius midshaft in the calcitonin + anabolic group (P = 0.05), but in the calcitonin only group this decrease was significant at the level of 0.01. Thus, intermittent administration of calcitonin in small doses (350 U/month), in combination with calcium (500 mg/die) and norandrostenolone decanoate (50 mg/month), seems to be a promising, relatively inexpensive therapeutic regimen in the treatment of established postmenopausal osteoporosis.
References
1. Chesnut CH (1984) Synthetic salmon calcitonin, diphosphonates and anabolic steroids in the treatment of postmenopausal osteoporosis. In: Christiansen C, Arnaud CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL (eds) Osteoporosis. Copenhagen, pp 549-555 2. Riggs BL, Hodgson SF, O'Fallon WM, Chao EYS, Wahner HW, Muhs JM, Cedel SL, Melton LJ III (1990) Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 322:802-809 3. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, Licata AA, Ross P, Woodson GC III, Yanover MJ, Mysiw J, Kohse L, Rao MB, Steiger P, Richmond B, Chestnut CH III (1990) Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 323:73-79 4. Barnett E, Nordin BEC (1961) Radiological assessment of bone density. Br J Radiol 34:683--698 5. Krasznai I, Lakatos P, Horv~ith Cs, Holl6 I (1987) Precision of estimation of bone mineral content by single and dual photon absorptiometry in longitudinal studies. J Nucl Med 26:212-213 (Congress ed) 6. Zstli J, SzOcs J, Steczek K, Szathmftri M, Kollin/~, Horv~ith Cs, Guoth M, Holl6 I (1983) Decreased calcitonin reserve in accelerated postmenopausal osteoporosis. Horm Metab Res 17:696-697 7. Holl6 I, Boross M, Sz~cs J (1971) Sex hormone deficiency and calcitonin sensitivity. Lancet II:1205-1206 8. Holl6 I, Fehtr T, Szfics J (1970) Serum dehydroepiandros-
10
9. 10. 11. 12.
13.
J. Sziics et al.: Three-Year Calcitonin Combination Therapy for Osteoporosis terone, androsterone and cortisol level in primary postmenopausal and other type osteoporosis. Acta Med Acad Sci Hung 27:155-160 Marshall DH, Crilly P.G, Nordin BEC (1977) Plasma androstendione and oestrone levels in normal and osteoporotic postmenopausal women. Br Med J 2:tt77-1t79 Holt6 I, Boross M, Szfics J (1975) Effect of sex hormone deficiency on calcitonin-induced hypocalcaemia. Acta Gerontol 5:609--616 Holm I, Sziics J, Steczek K (1971) Effect of norandrostenolone decanoate on calcium tolerance curves of patients with primary osteoporosis. Endokrinologie 58:326-330 Szfics J, Holl6 I, Guoth M (1984) Calcitonin in pathological postmenopansat osteoporosis: theory and practice. In: Christiansen C, Arnaud CD, Nordin BEC, Parfitt AM, Peck WA, Riggs BL (eds) Osteoporosis. Copenhagen pp 693-694 Sziics J, Holl6 I, Guoth M, Horv',ith Cs, Horv~tth K, Kollin (1986) Long-term intermittent, small dose calcitonin in menopausal osteoporosis. In: Delmas PD, Meunier PJ, Cohn DV
14. 15.
t6.
17. 18.
(eds) IXth ICCRH and Bone Metabolism (abstract 874) Nice, France Hirsch PF (1968) Enhancement of hypocalcemic activity of thyrocalcitonin by inorganic phosphate. In: Symposium on thyrocalcitonin and the C-cells. Heineman Ltd, London p 11 Raisz LG, Dietrich JW, Maina D (1975) Effects of phosphate on bone formation and resorption in tissue culture. In: Avioti L, Bordier Ph, Fleisch H, Massry S, Slatopolsky E (eds) Phosphate metabolism kidney and bone. Nouvelle Imprimerie Fournir, Toulouse pp 213-221 Rasmussen H, Bordier Ph, Marie P, Auquier L, Eisinger JB, Kuntz D, Caulin F, Argemi B, Gueris J, Julien A (1980) Effect of combined therapy with phosphate and catcitonin on bone volume in osteoporosis. Metab Bone Dis Rel Res 2:107-111 Kanis JA (1984) Treatment of osteoporotic fracture. Lancet I:27-33 Itoi E, Sakurai M, Mizunashi K, Sato K, Kasama F (1990) Long-term observations of vertebral fractures in spinal osteoporotics. Calcif Tissue Int 47:202-208
Calcified Tissue International 9 1992 Springer-Veflag New York Inc.
Clinical Investigations Three-Year Calcitonin Combination Therapy for Postmenopausal Osteoporosis with Crush Fractures of the Spine Jfinos Sziics, Csaba Horv~ith, l~va Kollin, Mikl6s Szathmfiri, and Istvfin Holl6 I st
Department of Medicine, Semmelweis University Medical School, Budapest, Korfinyi S. u. 2/a. 1083-Hungary
Received July 7, 1990, and in revised form February 5, 1991
Summary. Forty-five postmenopausal osteoporotic women with at least one osteoporotic vertebral crush fracture were randomized into three treatment groups. Each patient was on calcitonin, 50 U, on alternate days for 2 weeks monthly (350 U/month), and 500 rag/day oral calcium supplementation. In group II, this therapy was supplemented with phosphate (750 mg/day), and in group III, norandrostenolone decanoate (50 mg/month) was added to the calcitonin + calcium therapy. Bone mineral content, by single photon absorptiometry, of the radius midshaft and distal site (3 cm), as well as the lumbar and metacarpal radiomorphometrical indices were estimated semiannually. The therapeutic trial lasted 36 months except in the phosphate supplementation group, where, due to unfavorable results, treatment was discontinued after 24 months. Calcitonin practically prevented further bone loss for 24 months even in this relatively small and intermittent dosage. Phosphate supplementation was without benefit; however, according to the majority of the examined parameters, combination of calcitonin with the anabolic steroid norandrostenolone decanoate extended efficacy up to 36 months. This latter combination seems to be a promising, relatively inexpensive therapeutic regimen in the treatment of established postmenopausal osteoporosis. Key words: Postmenopausal osteoporosis - Small-dose calcitonin - Norandrostenolone decanoate - Intermittent ad-
ministration.
Menopausal osteoporosis is one of the biggest challenges to public health. Early diagnosis is difficult: the new, more sensitive methods (quantitative computed tomography, photon absorptiometry) are expensive and are not available everywhere. Prevention with elevated dietary calcium ingestion and exercise is generally accepted but often not sufficient. Estrogen therapy is primarily preventive and is not without hazards, even in an at-risk population. The therapy for established osteoporosis (i.e., generalized osteoporosis causing crush fractures of the spine) is still under debate. Calcitonin is often used but high costs and diminishing results in the second year of therapy [1] limit its
Offprint requests to: J. Szfics
value. Sodium fluoride stimulates bone formation--mainly at the axial rather than the peripheral skeleton--without decreasing the risk of vertebral crush fractures but increasing the number of nonvertebral fractures [2]; cyclical use of etidronate [3] seems to be a promising but still not widespread method. The aim of our trial was threefold: (1) to elaborate on a relatively inexpensive schedule using calcitonin in small doses, and with periodical administration; (2) to check the efficacy of our schedule over a period of 2-3 years; and (3) to establish if combination with other agents has any benefit on calcitonin monotherapy.
Patients and Methods Treatment was initiated on 45 postmenopausal women (aged 49--69, mean: 59.5 years) with established osteoporosis, i.e., besides osteoporosis, at least one osteoporotic crush fracture of the dorsolumbar spine was present without significant trauma or any other known reason. Detailed clinical examinations excluded hepatic, renal, hematological or malignant diseases, diabetes mellitus, or other endocrine disorders, Hyperparathyroidism was excluded by measuring serum calcium (total and ionized), phosphate, and C-terminal parathormone level and by determining tubular phosphate reabsorption. Normal serum 25-hydroxycholecalciferol levels and normal urinary output of calcium excluded osteomaiacia or hypercalciuric osteopenia. Informed consent was always obtained. Before treatment, a bidirectional X-ray film was taken of the dorsolumbar spine, both hands and femurs, and radiomorphometrical indices according to Barnett and Nordin [4] were calculated. Bone mineral content was measured on the midshaft and distal (3 cm) site of the nondominant radius with a Norland-Cameron 178 single photon densitometer. Results were received as the mean value of five parallel measurements. Long-time precision in our laboratory was 0.9% in phantom experiments [5]. Before therapy, total blood count, urinalysis, ionogramme, serum GOT, gamma GT, alkaline phosphatase, creatinine, total protein and electrophoresis, and postprandial blood glucose were measured by routine methods mainly on a Hitachi auto-analyzer. Serum calcium, phosphorus, and 24-hour urinary output of calcium were measured by atomic absorption spectrophotometry, and ionized calcium was determined with an Orion Space Stat unit. Radioimmunoassay methods were used for hormonal determinations (T-4, PTH, calcitonin, cortisol, 25-hydroxycholecalciferol). To monitor side effects of the treatment, laboratory checkups and clinical examinations were carried out monthly in the first year and bimonthly in the second and third years. Hormonal determinations as well as radiological examinations were done semiannually.
J. Sz~lcs et al.: Three-Year Calcitonin Combination Therapy for Osteoporosis
8
Rodfus midshoft
%
NETACAf?PAL RAD/OMORPHOMETR/CALINDICES" (M I I )
I10 %
100
l
..... ~.......... ~
~ ' ' ~ .......
90.
% 90,
80-
~2
"
80 6
t2
18 24 30 Radius distot (2cm)
36 months
%
6
110]
I2
18
24
30
36
months
LUMBAR B/CONCAVfTY RADfOMORPHOMETR/CALINDICES (L ZIZ) %
100
flO
}', '+' 3 80
lit
100
I~ 90.
6 12 t8 24 30 36 months Fig, 1. Single photon absorptiometry of patients with postmenopausal osteoporosis. Results are expressed as percentage of initial values (mean, standard deviation). Significant change (*P < 0.05; **P < 0.01) from initial values. ( ~ ) C; (--) C + P; ( . . . . . ) C+A.
Statistical analysis included Student's t test within the groups and analysis of variance (ANOVA) between the groups.
Therapy Unrestricted diet was supplemented with Calcium Sandoz tablets 500 mg daily. Each patient was on Miacatcic (Sandoz), 50 U, every other day for 2 weeks per month followed by a 2-week pause (i.e., seven injections = 350 U/month). Patients were randomized into three groups. Patients in group I received ealcitonin only, in group II therapy was supplemented continuously with phosphate (Phosphor Forte, Sandoz, 750 mg/day), and in group III, norandrostenolone decanoate injections (Retabotil, Richter, 50 rag) were administered monthly in addition to calcitonin. Within 2 years, 2 dropouts occurred: 1 from group II after 1 year due to nausea, and 1 from group Ill after 18 months due to a car accident. In the third year, therapy was terminated in the case of" 1 patient in group Ht because of nausea. Three patients each, completely symptom free, from groups I and III asked for discontinuation for nonmedicat reasons. As we planned to treat patients with advanced osteoporosis for 2 or 3 years, the untreated control group was omitted for ethical reasons. Results were evaluated for 43 patients.
Results There was no significant bone loss during the first 2 years of therapy in group I (calcitonin alone) and in group III (calci-
60
6
12
18
24
30
36
months
Fig. 2. Radiomorphometrical indices of patients with postmenopausal osteoporosis. Results are expressed as percentage of initial values (mean, standard deviation). Significant change (*P < 0.05; **p < 0.01) from initial values. (- ) C; (--) C + P; ( . . . . . ) C+A.
tonin + anabolic steroid). The rate of bone loss--if a n y - was very slow compared with what would be expected in this female population. Combination with phosphate was without benefit: a slight decrease was detected, which became statistically significant at months 18 and 24, therefore, this form of combination was discontinued after 24 months. Figures represent results expressed as a percentage of the initial values. A slight decrease was observed for group I (calcitonin only) in the third y e a r b u t c o m b i n a t i o n with n o r a n drostenolone nearly maimained efficacy. Using ANOVA, we could not find any stmistically significant difference among the groups. Taking single photon absorptiometry at the radius midshaft, a significant (t = 3.00, P < 0.05) decrease was already registered for group II at I8 months. I n the two other groups, bone mineral content was almost stable and the decrease was statistically significant only at 36 months (group I: t = 3.67, P < 0.01; group HI: t = 2.74, P < 0.05). On the distal radius, the change was never significant in the case of group III, whereas for group I, the decrease was significant at 36 months (t = 3.44, P < 0.01). By radiomorphometry, the changes in femoral indices were very slight, without significance in all groups (no fig-
J. Szfics et al.: Three-Year Calcitonin Combination Therapy for Osteoporosis ure). During the whole period, metacarpal indices slightly increased in groups I and III but not in group II. Lumbar biconcavity indices decreased in group I from 18 months (t = 2.90, P < 0.05), but in group III, no significant decrease occurred. The analgesic effect of calcitonin was remarkable even after the first week: patients reported diminishing pains, an effect that lasted during the 2-week pause and during the whole trial. During the 1,396 patient-months on therapy, only two new crush fractures occurred: one in the first month of therapy (group III) and one in the 20th month (group II). Patients reported diminishing height (4-14 cm) in the years before therapy. This reduction stopped almost completely during therapy. Treatment for group II was terminated after 2 years because of unfavorable results compared with the other two groups. Side effects were rare and minimal. In some cases, patients reported flushes a few minutes after injections, mainly on the chin and ear, and sometimes mild nausea which disappeared spontaneously. Routine laboratory findings were always within normal limits. No significant changes were o b s e r v e d in serum calcium, p h o s p h a t e , alkaline phosphatase, or parathyroid hormone levels.
Discussion
Previous observations in menopausal women with osteoporosis disclosed decreased reserve capacity [6], biological half-life, or efficacy of calcitonin [7] due to decreased adrenal androgen production. Serum levels of dehydroepiandrosterone sulfate [8] and androstendione [9] were decreased. In animal experiments [10] and in osteoporotic women [11], norandrostenolone decanoate restored calcitonin sensitivity. These observations raised the possibility that combination with norandrostenolone may enhance the antiresorptive effect of calcitonin on the bone. Moreover, the main problems with calcitonin therapy are the high cost of treatment and the inconvenience of injections. To obtain a better cost-benefit ratio and better acceptance we used relatively small doses, and the form of administration was intermittent, requiring seven injections monthly. Our preliminary results [12, 13] suggested some benefit to this combination in the therapy of postmenopausal osteoporosis. It is well known that phosphate may enhance the hypocalcemic effect of calcitonin [14]. There are data on the direct action of phosphate in promoting osteoblast activity and bone formation [15]. A combined phosphate-calcitonin therapy for osteoporosis was suggested previously [16]. As we planned our therapeutic trial for 2-3 years, and omitted a placebo-treated group for ethical reasons, we decided to administer phosphate, which, similar to androgens (anabolics), may also enhance calcitonin effect. Comparing the results of these three forms of therapy (the two combinations and calcitonin monotherapy), we unfortunately found the combination of calcitonin with phosphate in our study to be without benefit. The aim of osteoporosis therapy is to reduce fracture risk. To evaluate the effect of a special therapy from this point of view is difficult [17], because consecutive crush fractures of the spine in a patient often follow years later. However, only two new crush fractures in 1,396 patientmonths suggest at least some effect. This result is even better if we consider that the first crush fracture occurred in the first month of therapy and the other one developed in the phosphate-calcitonin group, which seemed to us to be an
unfavorable combination. In comparing our results with a recent study, the difference is striking: Itoi et al. [18] found a fracture rate of 41/100 patient years in osteoporotic women on 1 alfa hydroxyvitamin D3, whereas we found only 2/116 patient years. In the study of Watts et al. [3], the vertebral fracture rate was approximately 13/100 patient years in the placebo-treated group and 4.2/100 in those who were on etidronate. The analgesic effect of calcitonin was noteworthy: we think that this was one of the most important reasons why patients liked this form of therapy. Perhaps it is an explanation for the good compliance or for the few dropouts. Results obtained in this 36-month study strongly suggest that calcitonin, even in small doses, is a safe and effective antiresorptive therapeutic agent, at least for 2 years. In the calcitonin only and in the calcitonin + anabolic groups, of the five radiological parameters (two single photon absorptiometry, three radiomorphometry), only the lumbar biconcavity index decreased significantly in the calcitonin only group; the others did not. Combination with an anabolic steroid, norandrostenolone was again without side effects and extended efficacy for up to 3 years. Bone mineral content did not increase but the decrease was very slow, the pains of the patients diminished, and new crush fractures or other fractures did not occur. At the end of this 3-year study, the metacarpal and femoral radiomorphometrical indices did not change significantly: this was the case in the calcitonin + anabolic group with the single photon absorptiometry of the distal radius. A small but significant decrease occurred at the radius midshaft in the calcitonin + anabolic group (P = 0.05), but in the calcitonin only group this decrease was significant at the level of 0.01. Thus, intermittent administration of calcitonin in small doses (350 U/month), in combination with calcium (500 mg/die) and norandrostenolone decanoate (50 mg/month), seems to be a promising, relatively inexpensive therapeutic regimen in the treatment of established postmenopausal osteoporosis.
References
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