Q J Med 1999; 92: 143-150
© 1999 Association of Physicians
Effect of calcitonin on vertebral and other fractures
From the Centre for Metabolic Bone Diseases (WHO Collaborating Centre), University of Sheffield Medical School, Sheffield, UK
Received 27 November 1998
Professor J.A. Kanis, Centre for Metabolic Bone Diseases (WHO Collaborating Centre), University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX
 |
Summary |
|---|
 Top Summary IntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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.5–20
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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 |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
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.
|
References |
|---|
|
TopSummaryIntroductionMethodsResultsDiscussionAcknowledgementsAppendixReferences |
|---|
1. Cardona JM, Pastor E. Calcitonin versus etidronate for the treatment of postmenopausal osteoporosis: A meta-analysis of published clinical trials. Osteoporosis Int 1998; 7:165–74.
2. Plosker GL, McTavish D. Intranasal calcitonin (salmon calcitonin): A review of its pharmacological properties and role in the management of postmenopausal osteoporosis. Drugs Aging 1996; 8:378–400.[Web of Science][Medline]
3. Wallach S, Farley JR, Baylink DJ, et al. Effects of calcitonin on bone quality and osteoblastic function. Calcif Tissue Int 1993; 52:335–9.[Medline]
4. Burckhardt P, Burnand B. The effect of treatment with calcitonin on vertebral fracture rate in osteoporosis. Osteoporosis Int 1993; 3:24–30.[Medline]
5. Overgaard K, Hansen MA, Jensen SB, Christiansen C. Effect of salcatonin given intranasally on bone mass and fracture rates in established osteoporosis. A dose-response study. Br Med J 1992; 305:556–61.
6. Stock JL, Avioli LV, Baylink DJ, Chesnut C, Genant HK, Maricic MJ, Silverman SL, Schaffer AV, Beinblatt J, for the PROOF study group. Calcitonin-salmon nasal spray reduces the incidence of new vertebral fractures in postmenopausal women: three year interim results of the PROOF study. J Bone Miner Res 1997; 12 (suppl 1):S149.
7. Rico H, Hernandez ER, Revilla M, Gomez-Castresana F. Salmon calcitonin reduces vertebral fracture rate in postmenopausal crush fracture syndrome. Bone Miner 1992; 16:131–8.[Web of Science][Medline]
8. Rico H, Revilla M, Hernandez ER, Villa LF, Alvarez de Buergo M. Total and regional bone mineral content and fracture rate in postmenopausal osteoporosis treated with salmon calcitonin. A prospective study. Calcif Tissue Int 1995; 56:181–5.[Web of Science][Medline]
9. Arnala I, Saastamoinen J, Alhava EM. Salmon calcitonin in the prevention of bone loss at perimenopause. Bone 1996; 4:629–32.
10. Agrawal R, Wallach S, Cohn S, Tessier M, Verch R, Hussain M, Zanzi I. Calcitonin treatment of osteoporosis. In: Calcitonin 1980. Proceedings of an international symposium held in Milan, October 1980. Amsterdam, Excerpta Medica, 1980:237–46.
11. Ellerington MC, Hillard TC, Whitcroft SIJ, Marsh MS, Lees B, Banks LM, Whitehead MI, Stevenson JC. Intranasal salmon calcitonin for the prevention and treatment of postmenopausal osteoporosis. Calcif Tissue Int 1996; 59:6–11.[Web of Science][Medline]
12. Gennari CL, Chierichetti SM, Bigazzi S, Fusi L, Gonelli S, Ferrara R, Zacchei F. Comparative effects on bone mineral content of calcium and calcium plus calcitonin given in two different regimens in postmenopausal osteoporosis. Curr Ther Res 1985; 38:455–64.
13. Healey JH, Paget SA, Williams-Russo P, Szatrowski TP, Schneider R, Spiera H, Miltnick H, Ales K, Schwartzberg P. A randomised controlled trial of salmon calcitonin to prevent bone loss in corticosteroid-treated temperal arteritis and polymyalgia rheumatica. Calcif Tissue Int 1996; 58:73–80.[Web of Science][Medline]
14. Perez MA, Garcia FJB, Clabozo M, et al. Estudio comparativo multicentries de la calcitonina sintetica de salmon administrada por via nasal en el tratamiento de la osteoporosis post-menopausica establecida. Ann Med Intern 1995; 12:12–16.
15. Ringe J-D, Welzel D. Salmon calcitonin in the therapy of corticosteroid-induced osteoporosis. Eur J Clin Pharmacol 1987; 33:35–9.[Medline]
16. Ringe JD. Behandlung der primaren Osteoporosis mit Calcium und Lachscalcitonin. Dtsch Med Wschr 1990; 115:1176–82.[Medline]
17.
Sambrook P, Birmingham J, Kelly P, Kempler S, Nguyen T, Stat M, Pocock N, Eisman J. Prevention of corticosteroid osteoporosis. A comparison of calcium, calcitriol and calcitonin. N Engl J Med 1993; 328:1747–52.
18. Gruber HE, Ivey JL, Baylink DJ, Matthews M, Nelp WB, Sisom K, Chesnut CH. Long-term calcitonin therapy in postmenopausal osteoporosis. Metabolism 1984; 33:295–303.[Web of Science][Medline]
19.
Luengo M, Pons F, Martinez de Osaba MJ, Picado C. Prevention of further bone mass loss by nasal calcitonin in patients on long-term glucocorticoid therapy for asthma: a two year follow up study. Thorax 1994; 49:1099–102.
20. Peyron R, Serrurier D, Edouard C, Ghozlan R, Mayoux-Benhamon A, Meunier PJ. Treatment of high remodelling vertebral osteoporosis with human calcitonin: a two year double-blind placebo-controlled trial in 93 patients. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen, Osteopress, 1990:1430–3.
21. Mazzuoli G, Gennari C, Passeri M, Acca M, Camporeale M, Pioli G. Hip fractures in Italy: epidemiology and preventive efficacy of bone active drugs. Bone 1994; 14 (suppl. 1):S81–4.
22. Kanis JA, Johnell O, Gullberg B, Allander E, Dilzen G, Gennari C, Lopes Vaz AA, Lyritis G, Mazzuoli G, Miravet L, Passeri M, Perez Cano R, Rapado A, Ribot C. Evidence for the efficacy of drugs affecting bone metabolism in the prevention of hip fracture. Br Med J 1992; 305:1124–8.
23. Royal College of Physicians. Clinical guidelines for strategies to prevent and treat osteoporosis. London, Royal College of Physicians, 1998.
24. World Health Organisation. Guidelines for preclinical evaluation and clinical trials in osteoporosis. Geneva, WHO, 1998.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Qaseem, V. Snow, P. Shekelle, R. Hopkins Jr., M. A. Forciea, D. K. Owens, and for the Clinical Efficacy Assessment Subcommittee Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the American College of Physicians Ann Intern Med, September 16, 2008; 149(6): 404 - 415. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. MacLean, S. Newberry, M. Maglione, M. McMahon, V. Ranganath, M. Suttorp, W. Mojica, M. Timmer, A. Alexander, M. McNamara, et al. Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis Ann Intern Med, February 5, 2008; 148(3): 197 - 213. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Marcus, M. Wong, H. Heath III, and J. L. Stock Antiresorptive Treatment of Postmenopausal Osteoporosis: Comparison of Study Designs and Outcomes in Large Clinical Trials with Fracture as an Endpoint Endocr. Rev., February 1, 2002; 23(1): 16 - 37. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. E. Manson and K. A. Martin Postmenopausal Hormone-Replacement Therapy N. Engl. J. Med., July 5, 2001; 345(1): 34 - 40. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||