Gynecol. Endom'nol. 6 (1992) 141-147

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G. M . Prelevic and E . Y . Adashi* Division ofEndocrinology, Department ofMedicine, University Medical Center 'Zvezdara', Belgrade University School of Medicine, Belgrade, Yugoslavia; *Division of Reproductive Endocrinology, Department of Obstetrics and Gynecology, University of Maryland, Baltimore, USA Key words: POSTMENOPAUSAL OSTEOPOROSIS, CALCITONIN, BONEMASS,BONELOSS, ESTROGENS, BONE PAIN

ESTROGEN DEFICIENCY AND BONE LOSS that the physiological effect of estrogen is on osteoblasts7.*.However, in vivo data suggest the existence of estrogen effects on osteoclasts and a resultant inhibition of bone resorption. An alternative hypothesis suggests that estrogens act indirectly via other calcium-related factors such as calcitonin'. While some in vitro and human studies have shown the stimulative effect of estrogens on calcitonin secretion'@'*, others have reported opposite finding^'^'^. In spite of the well-documented role of estrogen deficiency in postmenopausal bone loss, it has been observed that estrogen replacement therapy is not associated with complete elimination of fracture~~.'~.'', pointing to the multifactorial origin of the disorder. In addtion to sex and menopause, numerous risk factors associated with osteoporosis have been establishedsuch as low body weight, fiir slun, low calcium intake, smolung, alcohol consumption, diabetes mellitus and a sedentary lifestyle. However, it became clear that, in the early menopausal period, the aim of treatment is to stabilizebone tissue, i.e. to reduce the rate of bone

It was Albright in 1941' who observed 50 years ago that the majority of patients with osteoporotic fi-actureswere postmenopausal women. Based on that observation,he was the first to hypothesize that osteoporosis is the result of estrogen deficiency. Although a reduction in total body mass may there is begin in the years prior to little doubt that the process is accelerated as a result of estrogen deficiency brought about by the menopause. Aitken and colleagues4have shown that women 3 years after oophorectomy had a mean bone mass significantly lower than women of the same age who had undergone hysterectomy with ovarian conservation.However, in spite ofthe obvious estrogen deficiency which occurs at menopause, it has been noted that not all women lose the same amount of bone mass5. In spite of the numerous data documenting the reduction of bone mass concomitant with the cessation of ovarian &nction4,as well as the prevention of bone loss with estrogen replacement6,it is still not clear how the estrogen effect on bone is mediated. It has recently been demonstrated that osteoblasts express estrogen receptors, suggesting

Correspondence: Dr G. M. Prelevic, 'Zvezdara', UniversityMedical Centre, Dimia-ija Tucovica 161,11000Belgrade, Yugoslavia

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Calcitonin and osteoporosis

resorption with slowing down of the overall bone turnover. That goal could be successfblly achieved with estrogen replacement, calcitonin administration, etc. In women with established osteoporosis, in the late postmenopausalyears, the main goal of treatment is to increase bone mass. It seems that none of the treatment modalities is effective in that respect and the restoration of osteoporotic skeleton appears to be very difficult. Thus it is well accepted that the prevention of postmenopausalbone loss is likely to be more successfd and thus more important than treatment.

ROLE OF CALCITONIN IN THE PATHOGENESIS OF POSTMENOPAUSAL OSTEOPOROSIS

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resorption, as well as its exact role in the pathogenesis of postmenopausal osteoporosis. It is still not clear how and to what extent the fall in calcitonin levels observed in the postmenopausal period is related to postmenopausal osteoporosis. The fact that pharmacological doses of calcitonin can slow bone 1oss32*35,36 does not necessarily indicate its pathogenic role. In the meantime, its application could be considered to be a pharmacological antiresorption treatment rather than a physiological replacement therapy.

CLINICAL STUDIES WITH CALCITONIN

Four types of calcitonin have been used in humans (porcine, human, salmon and eel) with varied therapeutic effectiveness ascribed to their dlfferent It has even been suggested that a relative deficiency of calcitonin could be responsible, at least in part, phannacokinetic properties. The most potent of all for the higher prevalence of symptomatic osteois salmon calcitonin which has a very low metabolic porosis among postmenopausal women18. Indeed, clearance rate and high receptor-ligand a i l i ~ ~ i t y ~ ~ . several studies have clearly demonstrated that Calcitonin has been evaluated for its utility in serum calcitonin levels are lower in women that in postmenopausal osteoporosis for almost 20 years. and circulating calcitonin decreases with Reports on its therapeutic effect are variable and advancingage20*22. That notwithstanding,reports to dif3icult to interpret as they vary in the calcitonin the contrary suggest an apparent lack of consensus dose applied, duration of treatment, methods used at this time'9*23. More recently, Reginster and colto assess the efficacy of treatment, etc. While some authors reported practically no effect on the osteoleagues have shown that postmenopausal women had a sigruficant reduction in serum calcitonin porotic p r o c e s ~ ~ others ~ . ~ have ~ , documented sign& icant increases in bone mass32935340-44. levels, suggesting that a reduction of the capacity to secrete calcitonin is a result of estrogen defiGruber and colleagues35compared a group receiving calcium and vitamin D supplements with a ciency. It has also been suggested that the protective effect of estrogens on the skeleton is mediated group also treated with calcitonin, and demonby the control of calcitonin synthesis and/or restrated an increase in total body calcium afier 18 lease25.Data on racial differences in calcitonin months (2.4%)in the group receiving calcitonin. level^^^.^' give additional support to its possible role They observed that the beneficial effect of calcitonin declined after 26 months (1.5%).Mazzuoli in the development of osteoporosis. Interestingly, and colleagues32reported a sigdcant increase a signtficant age-related reduction in the metabolic clearance rate of calcitonin has been documented2'. (13%)in bone mineral content of the distal radius after 12 months of treatment in 21 women with However, the functional [email protected] of this observation remains uncertain. postmenopausal osteoporosis treated with 100 U of salmon calcitonin on alternate days. The increment As postmenopausalosteoporosis is characterized in bone mass was linear for the first 6 months and by bone resorption in excess of formationz8,calcitonin is one of the promising agents for treatment, persisted over a year of therapy, while bone minas it is known to inhibit osteoclastic activity (bone eral content fell progressively in the control group r e s ~ r p t i o n )and ~ ~ stimulate *~~ bone f ~ r m a t i ~ nIt~ ~ .injected ~ ~ . with placebo. In a double-blind, placebohas also been documented that calcitonin increases controlled study, Overgaard and colleagues42 showed that nasal calcitonin is effective in the calcium absorption,which is most probably related treatment of established postmenopausal osteoto the increase in 1,25 dihydroxyvitamin D33334. However, evidence is still laclung on the physporosis. After 1 year of treatment they observed a iologicalrole of calcitonin in the regulation ofbone [email protected] decrease in bone mineral content in the

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placebo and control groups, while in the calciwomen with established postmenopausal osteotonin-treated group the changes were not sign& porosis is that calcitonin stops firther bone loss in those patient^^^*^^.^-. A few studies have reported cant. However, the biochemical parameters of both bone formation (osteocalcin) and bone rea significant increase in bone mass on calcitonin sorption (hydroxyproline) decreased significantly treatment-. An increase in bone mass docuduring calcitonin treatment. mented during the first 18 months of calcitonin It would appear that trabecular bone is more treatment is most probably the result of inhibition sensitiveto calcitonin treatment than corticalbone, of bone resorption without a corresponding inhisince most studies documented the largest increbition of bone f o r m a t i ~ n ~ ~ ~ ~ * . ment in bone mineral content at the level of the Civitelli and colleagues4’were able to document spine. One of the main reasons for these variable a highly significant increment of spinal bone minresults could be the heterogeneous nature of the eral content only in women with h g h bone tumdisorder. Recently, it has been shown that calciover, while osteoporotic patients with normal tonin is highly effective, resulting in a significant turnover neither gained nor lost bone mineral content during the treatment period. Obviously, increase in bone mineral content, only in postcalcitonin therapy is hghly effective in patients menopausal osteoporotic women with high bone with postmenopausal osteoporosis with high tumt u m o ~ e r ~In~the ’ ~ osteoporotic ~. patient with fiacover, resulting in a gain of bone mineral content of tures, calcitonin is of limited value in replacing bone w h c h has already been lost, although some the axial skeleton w h c h is mostly involved in the stu&es showed that it could be effe~tive~~,~~*‘Q~~+’. bone loss occurring after menopause. In order to prevent the development of secondAn increasing understanding of the osteoporotic ary hyperparathyroidism, the addtional adminisprocess has led us to the conclusion that the most tration oforal calcium is necessaTy5’. The usual dose appropriate indication for calcitonin is prevention of applied in most of the studies is 100 U of salmon osteoporosis, as its primary effect is inhibition of calcitonin given daily or on alternate days with bone resorption. The effect has been documented in several studies whch used calcitonin in recently 1-2 g of elementary calcium daily. It has also been suggested that the calcitonin effect in postpostmenopausal women36.45-49. Reginster and colmenopausal osteoporosis with vertebral fiactures is l e a g u e ~administered ~~ calcitonin intranasally at a dose-dependent, as women receiving higher doses dose of 50 U five times a week and observed, after showed greater increases in vertebral bone mineral 1 year of treatment, a gain in bone mass of 1.38 contenta. f 0.8% versus a loss ofbone mass of3.16 f 0.6% in the group not given calcitonin. Mazzuoli and colleaguesa observed that, in the group of women CALCITONIN AND BONE PAIN treated with calcitonin after ovariectomy, no sigBone pain ofien accompanies osteoporotic synnificant mo&fications of the skeletal mineral condromes and other bone &seases characterized by tent were observed during the 12-month excessivebone resorption. In t h s connection, it has treatment. Nencioni and P01vani~~also documented that the bone mass of the radius remained been observed that, besides its effect on bone mass, unchanged in recently postmenopausal women calcitonin (salmon calcitonin in particular) &splays during 12 months of treatment with calcitonin a sigmficant analgesic effect w h c h could be evident while a sigmficant reduction was observed in conas soon as the 2nd or 3rd week of treatmenf3. This trol women. Maclntyre and colleagues4’used calanalgesic effect of calcitonin increases with the citonin parenterally at a dose of 20-25 IU a week duration of treatment, the mechanism of action being seemingly distinct fiom the effect of the drug and compared results to those of different groups on bone tissue. Indeed, calcitonin receptors have treated with placebo, estrogen + progesterone, and been demonstrated in the cells ofthe limbic system. calcitonin + estrogen + progesterone. They found Moreover, the direct injection of calcitonin at the that calcitonin is more effective than estrogenlprolevel of the central nervous system of the rat, gesterone administration and also lacks the sideinduced behavioral changes and analgesia53. effects of those drugs. It has also been hypothesized that the analgesic The overall conclusion of numerous studes whlch have evaluated the effect of calcitonin in effect of calcitonin might be mediated by the

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endogenous opiate system (through an increase in P-endorphin ~ynthesis~~). An increase in P-endorphin levels is dose-related and more evident after intranasal than after parented administration of ~alcitonin~~. The improvement in pain relief was also greater with calcitonin nasal spray than with parenterally injected calcitonin. These findings suggest a direct central effect of calcitonin nasal spray, as nasal mucosa are close to the hypothalamic pain-regulating area56.

ANTIBODIES AND RESISTANCE TO CALCITONIN The issue ofpossible passive immunizationarose in connection with the problem of relative calcitonin resistance following prolonged therapy363’. At the end of 30 months of treatment with salmon calcitonin, Gruber and ~ o - w o r k e r swere ~ ~ able to detect antibodies in 17 out of 24 treated subjects (71%). However, they were unable to demonstrate conclusively that the appearance of antibodies correlates with the therapeutic e5cacy (orlack thereof) of calcit0nir-1~~. It has been documented that antibodies to heterologous synthetic calcitonins may be responsible for the resistance to treatment frequently observed in patients with Paget’s disease58.There are no data on the resistance to calcitonin treatment in postmenopausal osteoporosis. However, the observed gradual decrease in the skeletal response to calcitonin, which has been documented in women with postmenopausal osteoporosis after either U3’ or 18-24 months of continuous treatmed5, could be explained by antibody production to salmon calcitonin. Alternatively, it could be explained by the down-regulation of specific hormonal receptors. Similar phenomena have also been observed with other antiresorptive therapies,such as estrogens and androgens59.

SIDE-EFFECTS Side-effects of calcitonin treatment have been reported in up to 20% of treated patients. The most frequent side-effects are gastrointestinal (nausea, vomiting, abdominal pain, diarrhea) and vascular (flushing and tinghng of the hands) in Urinary frequency, headaches and skin rash have also been reportedM.Rarely, an unpleasant metallic taste as well as pain, or moderate idammatory

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reactions at the site ofinjection have been reported. Side-effects are dose-dependent and tend to decrease with the duration of treatment. If sideeffects do occur, they usually appear in the 1st month oftreatment and tend to disappeargradually thereafter. The most severe side-effects have been observed with intramuscular administration. Less severe side-effects have been observed when using the subcutaneous route. In the meantime, the main drawback to the use of calcitonin related to the route of administration has been successfullyovercome by nasal spray preparations61*”.Apart fiom a minor hcial flush, almost none of the side-effects have been documented with nasal spray application and the patients’ compliance is excellenp. Reginster and FranchimonP documented that intranasal administration of synthetic salmon calcitonin does not give rise to sideeffects even in patients known to be intolerant to calcitonin given by the intramuscular route.

CONCLUSION In spite of the numerous well-controlled studies demonstrating the preventive and therapeutic effectiveness of calcitonin in the context of postmenopausal osteoporosis, no data are available on the long-term effect of calcitonin on either bone mass or hcture incidence in a large population of appropriate patients. For example, Gruber and cow o r k e r ~observed ~~ a progression of vertebral compression fiactures over a 3-year period in some calcitonin-treated (but not control) patients, in spite of significantly increased total body calcium. In contrast, Gennari and colleagues40 reported fewer cases of new fiactures in calcitonin-treated (relative to untreated) patients (particularly in a group receiving the higher dose) over a period of 1 year. Obviously, several important questions still remain unanswered. One of the most important issues is: who should be offered hormonal treatment for the prevention of osteoporosis? A consensus paper suggests that hormone therapy should be offered to all women who are ‘at risk’” of develop ing postmenopausal osteoporosis. Although a large number of risk fictors have been demonstrated, we are s t i l l unable to estimate precisely who should receive preventive hormonal treatment. Reliable methods that will allow the clinician to identifjr those women who are at risk are still lacking.

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t o estrogens for osteoporosis prophylaxis, t o Which is the optimal time for the preventive administration of calcitonin? It is n o w clear that women with premature menopause (either sponestrogen treatment is effective in maintaining bone taneous o r surgically induced) in w h o m estrogen mass if started within 5 years of the m e n o p a u ~ e ~ . ~ ~replacement ,~~. is contraindicated. It should also be It seems reasonable to apply the same policy for suggested as the treatment of choice t o women calcitonin therapy. with pseudomenopause, receiving gonadotropin More clinical studes are needed t o answer the releasing hormone agonist therapy for either enimportant question o n how long calcitonin should dometriosis o r uterine fibroids for long periods, as be applied for prevention ofpostmenopausal osteowell as to older women (over 65 years) with porosis. It is expected that the cessation of treatfiactures. In the latter group, particularly, calciment may result in a rapid bone loss, as has already tonin treatment wdl be the most beneficial in been observed with estrogen therapy65. combination with agents capable of stimulating More studies with longer duration of follow-up bone formation. With the development of nasal and with dfferent treatment regimes are needed to spray calcitonin, its safety, lack of side-effects and assess the effective dose, whether it should be simple administration make it a most attractive agent for prophylaxis and treatment of postapplied continuously o r intermittently and how long patients should be treated. menopausal osteoporosis. Finally, synthetic salmon calcitonin could be strongly recommended, as an effective alternative

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9. Hillyard, C. J., Stevenson,J. C. and MacIntyre, I. (1978). Relative deficiency of plasma calcitonin in women. Lancet, 1, 961 10. Stevenson, C. J. (1985). Differential effects ofaging and menopause on C T secretion. In Pecile, A. (ed.) C'alcitonin 1984 - Chemistry, Physiology, Pharmacology and ClinicalAspects, p. 145. (Amsterdam,New Y ork, Oxford: Excerpta Medica) 11. Greenberg, C., Kukreja, S. C., Bowser, E. N., Hargis, G. K. and Henderson, G. A. (1986). Effects of estradiol and progesterone on calcitonin secretion. Endocrinology, 118, 2594 12. Agnusdei, D., Gonnelli, S., Montagnani, M.,Camporeale, A. and Gennari, C. (1989). Effects of one year treatment with estroprogestativeson calcitonin secretory reserve in postmenopausal osteoporotic patients. Cak$ Tissue. Int., 14 (Suppl.), 66 13. Lobo, R.A., Roy, S. and Shoupe, D. (1985). Estrogen and progestin effects on unnary calcium and calcitropic hormones in surgically-induced postmenopausal women. Horn. Metab. Res., 17, 3'70 14. Selby, P. L., Peacock, M., Barkworth, S . A., Brown, W. B. and Taylor, G. A. (1985). Early effects of ethinyloestradiol and norethisterone treatment in postmenopausal women on bone resorption and calcium regulating hormones. Clin. Sci., 69,265 15. Body,J. J., Struelens, M., Borkowski, A. and Mandart, G. (1989).Effects of estrogens and calcium on

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42. Overgaard, K., Riis, B. J., Christiansen, C., Podenphant,J. andJohansen,J. S . (1989).Nasalcalcitonin for treatment of established osteoporosis. Clin. Endom'nol., 30, 435 43. Overgaard, K., Hansen, M. A., Nielsen, V., Riis, B. J. and Christiansen, C. (1990). Discontinuous calcitonin treatment of established osteoporosis. A m . J . Med., 89, 1 44. Aloia,J. F., Niele, G., Culleton, J. and Vaswani, A. (1991). Treatment of osteoporosis with salmon calcitonin - clinical experience with 100 patients. A d v . Ther., 8, 36 45. Nencioni, T. andPolvani, F. (1985). Rationale for the use of calcitonin in the prevention of postmenopausal osteoporosis. In Pecile, A. (ed.) Calcitonin - Chemistry, Physiology, Pharmacology and Clinical Aspects, p. 297. (Amsterdam, New York, Oxford: Excerpta Medica) 46. Ortolani, S., Ferrari, A., Caraceni, M. P., Gussoni, A.M., Corghi, E., Motta, T. and Opolli, E. E. (1986). Calcitonin in surgical menopause. In Cecchetin, M. and Serge, G. (eds.) Calcitropic Hormones and Calcium Metabolism, p. 165. (Amsterdam: Excerpta Medica) 47. MacIntyre, I . , Whitehead, M. I., Banks, L. M., Stevenson, J. C., Wimalawansa, S. A. and Healy, M. J. R. (1988). Calcitonin for prevention ofpostmenopausal bone loss. Lancet, 1,900 48. Mazzuoli, G. F., Taboli, S., Big, F., Valtorta, C., Diacinti, D., Scameccha, L., Minisola, S., Bianchi,G., Piolini, M. and Dell'Acqua, S. (1989). Effects of salmon calcitonin on loss of bone mass induced by ovariectomy: controlled double-blind study. In Mazzuoli, G. F. (ed.) Calcitonin '88, p. 15. (Basle: Sandoz AG) 49. Prelevic, G. M., Balint-Peric, L. J. and Petrovic, J. (1990). The effects of intranasal salmon calcitonin on bone metabolism in women with premature menopause. Ann. N. Y . Acad. Sci., 592, 463 50. Rico, H., Espinos, D., DeRio, A. and Hernandez, E. L. (1986). Treatment of postmenopausal osteoporosis with calcitonin and calcium. Long-term results. In Osteoporosis: Second International Conference, p. 376. (Milan: Masson Italia Editori) 51. Eastell, R . and Riggs, L. B. (1987). New approaches to the treatment of osteoporosis. Clin. Obstet. Gynecol., 30, 860 52. Chesnut, C. H. (1989). Strategies for improving bone mass. In Peck, W. A. (ed.) Trends and Perspectives in the Diagnosis and Management of Osteoporosis, p. 51. (Camforth, UK: Parthenon Publishing) 53. Gennari, C. (1987).Calcitonins in osteogenic pain. In Christiansen, C., Johansen, J. S. and Riis, B. J. (eds.) Osteoporosis 1987, Vol. 2, p. 1256. (Copenhagen: Osteoporosis Aps.)

Gynecological Endocrinology

Prelevic and Adashi

54. German, C. and Agnusdei, D. (1988). Calcitonin in bone painmanagement. Curr. Ther. Res., 44,712 55. Overgaard, K., Agnusdei, D., Hansen, A., Maioli, E,.,Christiansen, C. and Gennari, C. (1991). Doseresponse bioactivity and bioavailability of salmon calcitonin in premenopausal and postmenopausal w0men.J. Clin. Endocrinol. Metab., 72, 344 56. Cllgiati, V. R., Guidobono, F. and Pecile, A. ('1983). Distribuzione e significato funzionale dei recettori per la calcitonina. In Gennari, C. and Segre, G. (eds.) The Efects of Calcitonin in Man, p. 33. (Milano: Masson) 57. Aloia,J. F., Vaswani, A,, Kapoor, A., Yeh, J. K. and Cohn, S. H. (1985). Treatment of osteoporosis with calcitonin, with and without growth hormone. Metabolism, 34, 124 58. Levy, F., M u g R., Dotti-Signst, S., Dambacher, M. A. and Fischer, J. A. (1988). Formation of neutralizing antibodies during intranasal synthetic salmon calcitonin treatment of Paget's disease. J . Clin. Endom'nol. Metab., 67, 541 59. Parfitt, A. M. (1980). Morphologc basis of bone mineral measurements: transient and steady state effects of treatment in osteoporosis. Min. Electrolyte Metab., 4, 273 60. Gennari, C., Cecchetin, M., Passeri, M., Francini, G., Gonnelli, S., Nami, R. and Bigazzi, S. (1983). Gli effetti collated di differenti calcitonine. In Gennari, C. and Segre, G. (eds.) Calcitonin in Man, p, 93. (Milan: Masson) 61. Kurose, H., Seino, Y., Shima, M., Tanaka, H., Ishida, M., Yamaoka, K. and Yabunchi, H. (1987). Intranasal absorption of salmon calcitonin. Calc$ Tissue. Int., 41, 249 62. Thamsborg, G., Storm, T., Sykulski, R., Brinche, E , Andersen, N. F., Hohegar:', S. N. and Soerensen, 0. H. (1988). Intranasal calcitonin and prevmtion of bone loss. Lancet, 1,413 63. Reginster, J. Y. and Franchimont, P. (1985). Sideeffects of synthetic salmon calcitonin given by intranasal spray compared with intramuscular injection. Clin. E x p . Rheumatol., 3, 155 64. National Institute of Health (1984). Consensus conference: osteoporosis.J. A m . Med. Assoc., 252, 799 65. Lindsay, R., MacLean, A., Kraszewsh, A., Hart, D. M., Clark, A. C. and Ganvood, J. (1978).Bone response to termination of estrogen treatment. Lancer, 1, 1325 66. Christiansen, C., Mazess, R. B., Transbol., I. and Finn Jensen, G. (1981). Factors in response to treatment of early postmenopausal bone loss. Calc$ Tissue. Znt., 33, 575

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Postmenopausal osteoporosis: prevention and treatment with calcitonin.

Gynecol. Endom'nol. 6 (1992) 141-147 Postmenopausal osteoporosis: prevention and treatment with calcitonin Gynecol Endocrinol Downloaded from informa...
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