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Effect of calcitonin on vertebral and other fractures

J.A. Kanis, E.V. McCloskey
DOI: http://dx.doi.org/10.1093/qjmed/92.3.143 143-150 First published online: 1 March 1999

Abstract

We examined the incidence of vertebral and non-vertebral fractures in published randomised clinical trials using calcitonin by parenteral injection or intranasal spray. Trials were reviewed that compared calcitonin with placebo, no therapy, or calcium with or without vitamin D, and that mentioned fracture as an outcome. Studies that compared the effect of calcitonin with other active treatments were excluded. Fourteen trials with 1309 men and women were identified. In the calcitonin and the control groups, vertebral and non-vertebral fractures were summed and divided by the number of individuals originally allocated to the treatment groups. The relative risk of any fracture for individuals taking calcitonin versus those not taking calcitonin was 0.43 (95% CI 0.38–0.50). The effect was apparent for both vertebral fracture (RR 0.45; 95% CI 0.39–0.53) and non-vertebral fractures (RR 0.34; 95% CI 0.17–0.68). When studies identifying patients with fracture, rather than numbers of fractures were pooled, the magnitude of effect was less (RR 0.74; 95% CI 0.60–0.93), and the separate effects on vertebral and non-vertebral fractures was of borderline significance. We conclude that, within the limitations of this study, treatment with calcitonin is associated with a significant decrease in the number of vertebral and non-vertebral fractures.

Introduction

A large number of controlled randomized trials have examined the effects of calcitonin on bone mass in pre-menopausal women, women at the time of the menopause and men and women with low bone mass, or osteoporosis.1 These studies indicate that the injection or intranasal application of calcitonin prevents bone loss in women at the time of the menopause, in the immediate post-menopausal period and in later life. Prevention of bone loss has been demonstrated at the spine, forearm and hip, though the greatest information is available for the spine. The effects appear to be quantitatively similar in prevention and in treatment, but the treatment-induced difference between placebo and calcitonin-treated patients is more marked the closer that the treatment is to the menopause. This is due to greater losses in the control wings of these studies, rather than to a difference in the effect of calcitonin.2

In contrast, there has been much less information available on the effects of calcitonin on the risk of vertebral and other osteoporotic fractures.3,4 A small randomized prospective study showed a significant effect of intranasal calcitonin when three dose groups were combined,5 and an interim analysis of a larger study suggests a decrease in vertebral fracture risk in one of three doses tested.6 Two other studies reported decreasing vertebral fracture frequency, but the number of patients with vertebral fractures was not given.7,8 Within the published literature there are however reports of fragility fractures occurring within the context of randomized control studies. The aim of the present study was to review these publications to determine whether a combined analysis might be used to test the hypothesis that calcitonin had no effect on fracture risk.

Methods

We searched the literature for randomized trials that compared calcitonin therapy with placebo, no therapy, or calcium supplements with or without the use of vitamin D. Trials were searched from Medline (1988 to 1996) conference proceedings (to the end of 1997), and reference lists of various review articles and books. Where appropriate, senior authors were contacted to answer specific queries. Languages accepted were English, German, Spanish, Italian and French. A minimum study duration of 6 months was accepted.

A total of 57 trials were identified that met the inclusion criteria. Of these, 41 did not mention in the paper whether or not fractures had occurred, and these were excluded from further analysis (see Appendix), leaving 16 relevant trials.520

In one trial, in perimenopausal women, no fractures occurred9 and it is included in the analysis. In two studies, fractures were mentioned, but details were not provided in the publications nor from subsequent correspondence. In one,14 fractures were said to be significantly fewer in calcitonin-treated patients compared with controls. The other study11 mentioned that fractures occurred but gave no details.

Because of the varying lengths of treatment and measurements used, and different methods for assessing vertebral fractures, a formal meta-analysis was not undertaken. In some instances publications reported variously the number of patients or the number of events. Wherever possible, we took the number of patients. The number of individuals allocated to the groups was used as the denominator. Relative risks were calculated with 95% confidence intervals.

Results

All but one study identified used synthetic salmon calcitonin. The exception20 used an intermittent regimen of human calcitonin. The dosage regimen and the route of administration varied markedly between studies (Table 1).

In those studies reporting the number of fractures, there were fewer vertebral and non-vertebral fractures in the group receiving salmon calcitonin than in the group who did not (Table 1). In calcitonin-treated patients, 237 vertebral fractures were reported in 1309 patients, and 271 vertebral fractures occurred in 678 placebo-treated patients, giving an apparent efficacy of 55% (RR 0.45; 95% CI 0.39–0.55). A comparable decrease in fracture burden was found adjusting for the duration of follow-up (6.94 vs. 16.56 fractures/100 patient-years, respectively). In those studies that identified the frequency of non-vertebral fractures, calcitonin was associated with a significant decrease in risk (RR 0.34; 95% CI 0.17–0.68). Overall, fracture risk decreased by 57% (Figure 1). The exclusion of men or the exclusion of any secondary cause of osteoporosis made no difference to the significance of these findings (RR 0.53; 95% CI 0.43–0.64).

Several studies reported vertebral fracture rates rather than the number of patients with fracture.7,8,10,20 When these studies were excluded, there was a decrease in the risk of vertebral fracture in calcitonin-treated patients compared to controls, but the magnitude of the decrease was less marked and of borderline significance. In the calcitonin-treated patients, 166/1190 patients developed a vertebral fracture, whereas a vertebral fracture occurred in 96/554 placebo-treated patients (RR 0.80; 95% CI 0.64–1.01). Calcitonin was also associated with a more marked but non-significant decrease in the proportion of patients with non-vertebral fractures (RR 0.48; 95% CI 0.20–1.15). The pooled estimate for both vertebral and non-vertebral fractures gave a relative risk of 0.74 (95% CI 0.60–0.93; Figure 1).

Discussion

The results of these pooled randomized data support the view that salmon calcitonin decreases the risk of vertebral and non-vertebral fractures. It is unlikely that the calculated odds ratios would have arisen by chance. There are, however, a number of limitations to consider.

Firstly, a large number of publications did not report the occurrence of fractures. It is possible, but unlikely, that no fractures occurred in these studies. It might also be the case that publication biases arose, in that studies with more fractures in the treated than control arm would be less likely to mention fractures in the report. Even if it is assumed that no publication bias occurred, but that some fractures occurred but were unreported, the degree of risk reduction of vertebral or other fractures cannot be computed from the present analysis.

A second source of bias may have arisen because several of the studies, although randomized, were open rather than double-blind. If patients on active treatment took additional steps to prevent fracture, a component of the effect could be due to contamination.

Thirdly, the duration of studies was relatively short and in only two did it exceed 2 years.6,9 The long-term effects on fracture frequency can therefore not be derived.

The effects of calcitonin on hip fracture rates have not been studied directly. Two case control studies21,22 analysed the effects of all types of calcitonin on hip fracture rates. Both showed evidence of reduced hip fracture risk comparing ever and never users of calcitonin. These two analyses were from the MEDOS study. In the case of the entire study, exposure to calcitonin was associated with a 30% decrease in hip fracture risk (RR 0.71, 95% CI 0.52–0.90), adjusted for previous intake of oestrogen. Many patients concurrently took calcium supplements, but independent effects of calcium and calcitonin were identified. The study also showed protective effects of estrogens but no protective effect of fluoride on hip fracture risk, and provided, therefore, a quasi-negative and -positive control. In the sub-analysis of the Italian centres21 a 53% decrease in risk was observed (RR 0.47; 95% CI 0.30–0.74) with a combination of calcitonin with calcium. The present study supports the view that the associations from case-control studies are causally related.

Calcitonin is one of the several therapeutic agents available for the management of osteoporosis.23 The ultimate arbiter of efficacy lies in studies of fracture rate.24 The dearth of randomized double-blind studies that address this question by modern standards, a reflection of the antiquity of calcitonin, means that conclusions concerning efficacy are inferential. Overall, fracture rates appeared to decrease by about 30% over and above the effects of calcium with or without vitamin D. This is a relatively small effect compared with recent experience with the bisphosphonates or raloxifene,23 although as mentioned the present study may give an unreliable estimate of the magnitude of effect. We conclude on the balance of probabilities that calcitonin decreases osteoporotic fracture rate but that it remains to be determined whether this can be shown `beyond a reasonable doubt'.

Acknowledgements

We are grateful to Dr M. Azria for his help with the literature search. Funded in part by the NHS R&D Health Technology Assessment Programme.

Appendix

Randomized trials of calcitonin compared to no treatment or treatment with calcium with or without vitamin D in which fracture was not mentioned as an outcome or side-effect.

Adachi JD, Bensen WG, Bell MJ, Bianchi FA, Cividino AA, Craig GL, Sturtridge WC, Sebaldt RJ, Steele M, Gordon M, Themeles GE, Tugwell P, Roberts R, Gent M. Salmon calcitonin nasal spray in the prevention of corticosteroid-induced osteoporosis. Br J Rheumatol 1997; 36:255–9.

Adami S, Baroni MC, Broggini M, Carratelli L, Caruso I, Gnessi L, Laurenzi M, Lombardi A, Norbiato G, Ortolani S. Treatment of postmenopausal osteoporosis with continuous daily oral alendronate in comparison with either placebo or intranasal salmon calcitonin. Osteoporosis Int 1993; 3: (suppl 3):S21–7.

Adami S, Passeri M, Broggini M, Carratelli L, Caruso I, Gandolini G, Gnessi L, Laurenzi M, Lombardi A, Norbiato G, Ortolani S, Pryor-Tillotson S, Reda C, Romanini L, Subrizi D, Wei L, Yates AJ. A comparison of oral alendronate and intranasal salmon calcitonin in the treatment of osteoporosis in postmenopausal women. Bone 1995; 17:383–90.

Beck-Jensen JE, Thamsborg G, Kollerup G, et al. Effect of nasal salmon calcitonin in established osteoporosis (abstract). Bone 1995; 16 (suppl):198S.

Crespo R, Revilla M, Crespo E, Villa LF, Rico H. Complementary medical treatment for Colles' fracture: a comparative, randomised longitudinal study. Calcif Tissue Int 1997; 60:567–70.

Flicker L, Hopper JL, Larkins RG, Lichtenstein M, Buirski G, Wark JD. Nandrolone decanoate and intranasal calcitonin as therapy in established osteoporosis. Osteoporosis Int 1997; 7:29–35.

Gennari C, Chierichetti SM, Gonnelli S, Piolini M, Francini G, Civitelli R, Agnusdei D, Montagnani M. Analgesic activity and side effects of different calcitonins in man. In: Pecile A, ed. Calcitonin. Holland, Elsevier, 1985:183–8.

Gennari C, Chierichetti SM, Bigazzi S, Fusi L, Gonnelli S, Ferrara R, Zacchei F. Comparative effects on bone mineral content of calcium and calcium plus salmon calcitonin given in two different regimens in postmenopausal osteoporosis. Curr Ther Res 1985; 38:455–64.

Gennari C, Agnusdei D, Montagnani M, Gonnelli S, Civitelli R. An effective regimen of intranasal salmon calcitonin in early postmenopausal bone loss. Calcif Tissue Int 1992; 50:381–3.

Gennari C, Agnusdei D, Camporeale A. Effect of salmon calcitonin nasal spray on bone mass in patients with high turnover osteoporosis. Osteoporosis Int 1993; (supple 1):S208–10.

Gonnelli S, Cepollaro C, Pondrelli C, Martini S, Rossi S, Gennari C. Ultrasound parameters in osteoporotic patients treated with salmon calcitonin—A longitudinal study. Osteoporosis Int 1996; 6:303–7.

Harju E, Punnonen R, Tuimala R, Salmi J, Paronen I. Vitamin D and calcitonin treatment in patients with femoral neck fracture: a prospective controlled clinical study. J Int Med Res 1989; 17:226–42.

Kollerup G, Hermann AP, Brixen K, Lindblad BE, Mosekilde L, Sorensen OH. Effects of salmon calcitonin suppositories on bone mass and turnover in established osteoporosis. Calcif Tissue Int 1994; 54:12–15.

Luengo M, Picado C, Del Rio L, Guanabens N, Montserrat JM, Setoain J. Treatment of steroid-induced osteopenia with calcitonin in corticosteroid-dependent asthma: a one-year follow-up study. Am Rev Respir Dis 1990; 142:104–7.

Lyritis GP, Magiasis B, Tsakalakos N. Prevention of bone loss in early nonsurgical and non-osteoporotic high turnover patients with salmon calcitonin: the role of biochemical bone markers in monitoring high turnover patients under calcitonin treatment. Calcif Tissue Int 1995; 56:38–41.

MacIntyre I, Stevenson JC, Whitehead MI, Wimalawansa SJ, Banks LM, Healy MJ. Calcitonin for prevention of postmenopausal bone loss. Lancet 1988; 1:900–2.

Mango D, Ricci S, Manna P, Natili G, Dell'Acqua S. Preventive treatment of cortical bone loss with salmon nasal calcitonin in early postmenopausal women. Minerva Endocrinol 1993; 18:115–21.

Mazzuoli G, Passeri M, Gennari C, Minisola S, Antonelli R, Valtorta C, Palummeri E, Cervellin G, Gonnelli S, Francini G. Effect of salmon calcitonin in postmenopausal osteoporosis: a controlled double-blind clinical study. Cacif Tissue Int 1986; 38:3–8.

Mazzuoli GF, Tabolli S, Bigi F, Valtorta C, Minisola S, Diacinti D, Scamecchia L, Bianchi G, Piolini M, Dell-Acqua S. Effects of salmon calcitonin on the bone loss induced by ovariectomy. Calcif Tissue Int 1990; 48:1–6.

Meschia M, Brincat M, Barbacini P, Crossignani PG, Albisetti W. A clinical trial on the effects of a combination of calcitonin (carbocalcitonin) and conjugated estrogens on vertebral bone mass in early postmenopausal women. Calcif Tissue Int 1993; 53:17–20.

Meunier PJ. Calcitonina intranasal para la prevencion de la osteoporosis post-menopausica. Rev Med Univ Navarra 1992; 37:200–4.

Nishizawa Y, Hagiwara S, Nakatsuma K, Aratani H, Miki T. Efficacy of low dose, intermittent eel calcitonin treatment for osteoporosis. J Bone Miner Metab 1995; 13:23–6.

Orimo H, Morii H, Inone T, Yamamoto K, Minaguchi H, Ishii Y, Murota K, Fujamaki E, Watanabe R, Harata S, Honjo H, Fujita T. Effect of elcatonin on involutional osteoporosis. J Bone Miner Metab 1996; 12:73–8.

Overgaard K, Riis BJ, Christiansen C, Hansen MA. Effect of salcatonin given intranasally on early postmenopausal bone loss. Br Med J 1989; 299:477–9.

Overgaard K, Hansen MA, Nielsen VAH, Riis BJ, Christiansen C. Discontinuous calcitonin treatment of established osteoporosis—effects of withdrawal of treatment. Am J Med 1990; 89:1–6.

Overgaard K, Christiansen C. Long-term treatment of established osteoporosis with intranasal calcitonin. Calcif Tissue Int 1991; 49: (suppl);S60–3.

Overgaard K, Riis BJ, Christiansen C, Podenphant J, Johansen JS. Nasal calcitonin for treatment of established osteoporosis: effects of withdrawal of treatment. Clin Endocrinol 1989; 30:435–42.

Overgaard K. Effect of intranasal salmon calcitonin therapy on bone mass and bone turnover in early postmenopausal women: a dose-response study. Calcif Tissue Int 1994; 55:82–6.

Perrone G, Galoppi P, Valente M, Capri O, D'Ubaldo C, Anelli G, Zichella L. Intranasal salmon calcitonin in postmenopausal osteoporosis: effect of different therapeutic regimens on vertebral and peripheral bone density. Gynecol Obstet Invest 1992; 33:168–71.

Reginster JY. Calcitonin for prevention and treatment of osteoporosis. Amer J Med; 1993;95: (suppl 5A):44s–7s.

Reginster JY, Denis D, Deroisy R, Lecart MP, DeLongueville M, Zegels B, et al. Long-term (3 years) prevention of trabecular postmenopausal bone loss with low-dose intermittent nasal salmon calcitonin. J Bone Miner Res 1994a; 9:69–73.

Reginster JY, Meurmans L, Deroisy R, Jupsin L, Biquet I, Albert A, Franchimont P. A 5-year controlled randomized study of prevention of postmenopausal trabecular bone loss with nasal salmon calcitonin and calcium. Eur J Clin Invest 1994b; 24:565–9.

Reginster JY, Deroisy R, Lecart MP, Sarlet N, Zegels B, Jupsin I, et al. A double-blind placebo-controlled dose-finding trial of intermittent nasal salmon calcitonin for prevention of postmenopausal lumbar spine bone loss. Am J Med 1995; 98:452–8.

Reginster JY, Albert A, Lecart M, Lambelin P, Denis D, Deroisy R, Fontaine M, Franchimont P. 1-year controlled randomized trial of prevention of early postmenopausal bone loss by intranasal calcitonin. Lancet 1987a; ii:1481–3.

Reginster JY, Mautalen C, Gennari C, Gaspar S, Deroisy R, Vandalem JL, Franchimont. Are antibodies against salmon calcitonin able to inhibit the biological efficacy of the drug? In: Christiansen C, Johansen JS and Riis BJ, eds. Osteoporosis 1987. The proceedings of the International Symposium on Osteoporosis. Copenhagen, Osteopress, 1987:916–18.

Resch H, Pietschmann P, Willvonseder R. Estimated long-term effect of calcitonin treatment in acute osteoporotic spine fractures. Calcif Tissue Int 1989; 45:209–13.

Rotolo F, Franceschini R, Galmarini V, Fioretta G, Romano P, Pasquarelli V. Valutazione dell'efficacia della calcitonina di salmone spray nasale nell'osteoporosis. Minerv ortop traumatol 1991; 42:495–8.

Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Pocock N, Eisman J. Prevention of corticosteroid bone loss. Osteoporosis Int 1993; (suppl 1):S141–3.

Thamsborg G, Storm TL, Sykulski R, Brinch E, Nielsen HK, Sorensen OH. Effect of different doses of nasal salmon calcitonin on bone mass. Calcif Tissue Int 1991; 48:302–7.

Thamsborg G, Jensen JEB, Kollerup G, Hange EM, Melsen F, Sorensen OH. Effect of nasal salmon calcitonin on bone remodelling and bone mass in postmenopausal osteoporosis. Bone 1996; 18:207–12.

van der Wiel HE, Lips P, Nauta J, Kwakkel G, Hazenberg G, Netelenbos JC, van der Vijgh WJF. Intranasal calcitonin suppresses increased bone resorption during short-term immobilization: a double-blind study of the effects of intranasal calcitonin on biochemical parameters of bone turnover. J Bone Miner Res 1993; 8:1459–65.

View this table:
Table 1

Effects of calcitonin on fracture in randomized control trials

StudyDose (IU)RouteDurationPopulationAge range or mean (years)Sample sizeCompleted study (n)Fractures
SpineOther
a Number of patients with fracture unknown. Data expressed as total number of fractures. b Excludes the two studies of Rico et al. for vertebral fracture. c 100 IU given for 10 days each month. d Patients given 1000 mg Ca plus 400 IU vitamin D. e Patients additionally given calcitriol 0.5–1.0 μg daily. f Human calcitonin four times weekly for four weeks out of each 10 weeks.
Gennari et al., 198512100 qdi.m/s.c1 yearPostmenopausal women with two or more crush fractures  59Total  15 4
100 od 82  15 6
  0  15 11
Overgaard et al., 19925 50nasal2 yearsPostmenopausal women with low bone mass (T-score <−2.0)  70 52  40  2 1
100 52  43  0 1
200 52  41  2 0
  0 52  40  6 2
Healey et al., 199613100qds.c2 yearsPatients starting costicosteroids for temporal arteritis and polymyalgia  45–87 25  19  2
  0 23  21  3
Ringe, 199016100 qds.c1 yearMen and women with osteoporosis  27–80 20  20  5 2
100 od 19  19  5 2
  0 20  20 11 5
Rico et al., 1992a7100ci.m2 yearsPostmenopausal women with two or more crush fractures  68 32  30 13 2
  0 28  27 29 4
Rico et al., 1995a8100ci.m2 yearsPostmenopausal women with one or more crush fractures  69 36  33 5
  0 36  35 31
Stock et al., 1997d6400nasal3 yearsPostmenopausal women with established osteoporosis  68312 278 46
200316 286 37
100316 272 46
  0311 296 55
Gruber et al., 1984d18100s.c2 yearsPostmenopausal women with established osteoporosis  65 24  22  6
  0  57–75 21  18  2
Luengo et al., 199419200 odnasal2 yearsAsthmatic men and women on glucocorticosteroids  49 22  17  2 1
  0 22  17  2 1
Arnala et al., 1996a100nasal3 yearsPerimenopausal women>40 60  50  0 0
  0 60  46  0 0
Agrawal et al., 1980d,a10100s.c2 yearsMen with established vertebral osteoporosis 68total   8  8 1
  0 39  17 38 9
Sambrook et al., 199317400enasal2 yearsMen and women taking glucocorticosteroids  51total  29  2 0
  0e  18–79103  34  1 1
  0  29  2 1
Peyron et al., 1980a200.25 mgfs.c2 yearsMen and women with established vertebral osteoporosisnot giventotal  48 46
  0279  45 77
Ringer & Welzel, 198715100 qds.c6 monthsSteroid-treated men and women  25–67 19  18  0 1
  0 19  18  3 2
CombinedbTest132723711
Control 67827125
Figure 1.

Relative risk of fracture associated with the administration of calcitonin in randomized controlled trials. The left-hand panel shows the effect of calcitonin on the number of fractures, and the panel on the right the effect on the number of patients with fracture.

References

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