British Mutual Bidltlin (1992) VoL 48, No. 2, pp. 458-468 © The Bnnih Council 1992
Future prospects for hormone replacement therapy J Reeve MRC Clinical Research Centre, Harrow, UK
To avoid the complication of osteoporosis, hormone replacement therapy (HRT) is now standard therapy in women with premature ovarian failure. The indications for HRT after the age of 50 are more controversial. There are strong indications from case-control studies that in N. America and Europe HRT protects against osteoporotic fracture, myocardial infarction and stroke; yet the evidence from case control studies is insufficiently precise to quantitate accurately the potential benefits that would accrue from its more widespread use. Clear guidelines also need to be established on the potential usefulness of selective prescribing of HRT using one or more screening procedures. The only effective way of achieving this and of quantitating the potential benefits of HRT with sufficient accuracy is by means of one or more randomized controlled trials. Future research will also address concerns such as the possible increase in the risk of breast cancer after 10 or more years of therapy. Critical to the more widespread acceptance of HRT may be the development of safe regimes which do not promote uterine bleeding as well as minimizing other unwanted side-effects.
It will be clear from reading the other contributions to diis number of the Bulletin that many scientific issues of substance remain to be resolved before the practising doctor can judge straightforwardly when to prescribe HRT and for how long. In many cases, the decision will be heavily influenced by the personal preference of the individual patient, who will make a choice based on the medical advice received. This will be weighed against the good
FUTURE PROSPECTS FOR HRT
459
and bad effects of HRT as she sees or experiences them. In this paper an attempt is made to identify the preconditions for a rational strategy for HRT use in a wider primary care and public health framework. WHY SHOULD HRT BE NECESSARY? The principal adverse consequences of menopause relate to its effects on the cardiovascular system and the skeleton as well as on the urogenital tract and subjective well-being, including cerebral function. However, with regard to the cardiovascular system and the skeleton, evidence that menopause leads to significant adverse health consequences comes largely from studies on affluent, westernized populations. Whereas postmenopausal bone loss appears to occur at similar rates in African as in European populations, there is evidence that age-adjusted rates of serious insufficiency fractures are at least an order of magnitude lower in some African populations.1 Likewise, cardiovascular disease secondary to atherosclerosis occurs at much lower rates in many third world than in typical western postmenopausal populations. Oriental populations also have lower rates. The secular trends in both osteoporotic fractures and myocardial disease evident over the last three decades in most western countries point to important environmental influences on these disorders which, at least until recently, have been growing increasingly adverse. These have little to do with the hormonal status of the women affected since age at menopause has changed almost imperceptibly in the last 100 years. Nor can simple clinical measurements, such as cholesterol levels or bone density indices, be used as measures of risk that can, for example, be transferred from an affluent western population to a third world population. A rational policy for combatting heart disease or osteoporosis will have to take into account local population characteristics, degrees of risk and, where appropriate, the local usefulness of clinical measurements in selecting women at particular risk. Accordingly, HRT is more likely to promote women's health in affluent westernized cultures than in third world subsistence cultures. The reasons why this should be so are profoundly interesting but are far from being understood. Inevitably, the reasons for the relatively poor, and recently worsening, skeletal and cardiovascular health of postmenopausal women in western cultures have been sought in their changing diets, exercise habits and consumption
460
HORMONE REPLACEMENT THERAPY
of tobacco. In Britain, energy consumption has fallen by an average of 18% in 2 decades,2 indicating reduced levels of physical activity. Smoking rates in women peaked after those in men;3 while diets have altered towards patterns adding to the risk of cardiovascular disease. THE CASE FOR SELECTIVITY An impressive finding of the survey among primary care physicians reported by Wilkes and Meade4 was the perceived need for guidance from further research on the risks and benefits of HRT. While about 60% of doctors would at present contemplate using HRT for prevention of cardiovascular disease or osteoporosis, they appeared to be prescribing selectively and only 7 to 10% of eligible women were receiving treatment. Whereas the personal preferences of women undoubtedly play a large part in the decision to treat, many wish to make their choice conditional on the balance of risks and benefits. Concern among patients about the relative risks of diseases such as osteoporosis, heart disease and breast cancer, which may be modified by HRT, may not accord with the prevalence of these diseases or with the death rates which are attributable to them. This is natural in view of the different degrees of suffering caused by each. Apart from this, many women are more concerned at age 50 about health issues in their sixth and seventh decades than in the diseases perceived to be of old age, such as hip fracture. In line with this, they regard postponement of an adverse effect, such as a myocardial infarct or fracture, as valuable particularly if it postpones long-term ill health or dependency. In general, most women at the age of menopause are seeking to optimize their healthy (disability-free) life expectancy (DFLE) rather than their total life expectancy. As Robine and Ritchie* have shown, this is only about 80% of total life expectancy in British women who on average, at age 50, can expect no more than 12-15 more years of DFLE. Locomotor disorders rank first and circulatory diseases second in the list of disease categories which circumscribe DFLE. The interests of agencies which fund health care may be rather different. Obviously, funding agencies are more concerned about costs of treatment than are insured patients. Besides that there is another point. A younger patient, for example, with a hip fracture may be cheaper to treat than an older one because the former is
FUTURE PROSPECTS FOR HRT
461
more likely to be suitable for an early discharge scheme.6 However, in view of the substantial costs7 of a policy of non-selective assignment to HRT, both patients and funding agencies have a considerable interest in the possibility of prescribing HRT selectively. SCREENING: FOR AND AGAINST It has been argued that screening for any sort of index of bone quantity is an inappropriate use of resources because of the poor selectivity of bone densitometry for women at risk of fracture.2 A recent study, however, has revealed that very much better estimates of vertebral fracture risk are obtainable than was previously thought possible,8 which makes it necessary to re-examine the question. Ross et al.9 collated a large number of studies estimating fracture rates in relation to bone density indices. Because of potential sources of bias the most valid data are likely to be prospective studies which have adjusted for age. The largest study examining hip fracture rates estimated that the relative risk of hip fracture for a 1 S.D. reduction in peripheral bone density, used as the sole measure of risk, ranged from 1.41 to 1.66 according to measurement site.10 Age was an independent predictor of hip fracture in this study, the risk doubling with each additional decade of age. For vertebral fractures a similar, rather stronger, relationship between bone mass and peripheral bone density indices was obtained by Ross et al.8 However, they also found that the existence of previous vertebral fractures was an additional, powerful predictor of further fractures. Relative to a woman with no spinal fractures in the highest tertile for calcaneal bone mass, a woman in the lowest tertile had a seven-fold increase in risk of a new fracture, but a 25-fold increase in risk if she had previously had a vertebral fracture. This was after adjusting for age, although age was no longer a statistically significant determinant of fracture risk when both bone mass and pre-study fracture prevalence were included in the model. In view of the relatively high prevalence of vertebral fractures from the 7th decade on, a spinal X-ray might be a practical additional means of assessing risk. Therefore, the means for identifying reasonably precisely the women at risk of a second or subsequent vertebral fracture based on two simple low dose radiological procedures may be available. A recent study by Cooper et al.11 suggests that about half of all patients suffering a vertebral fracture in Rochester, Minnesota, do
462
HORMONE REPLACEMENT THERAPY
not present for investigation and could only be identified by routine screening. This accords with other data suggesting that vertebral fractures have a long-term impact on health which depends substantially on how many vertebrae have been damaged. So an X-ray would have to be asked for with screening in mind in some cases. An argument that has been raised against screening using densitometry is that bone loss after the time of measurement may differ substantially between individuals. In the later post-menopause Hui et al. have found that rates of bone loss vary considerably and bear little relation to measurements of loss in the same individuals made in the early postmenopausal period.12 Nevertheless Hansen et al. in another long-term prospective study have suggested that women who lose bone more rapidly than average from the forearm can be predicted to have cumulatively lost more than their peers some 12 years after the menopause.13 This is to some extent the result of the fairly dramatic slowing of forearm bone loss; with the passage of time after menopause Hansen and colleagues found that about half the total loss occurs in the first 2-3 years. However, Hansen's suggestions13 that biochemical measurements may be used to predict the fast loser may be an example of biochemical 'overkill'. Since Hansen and colleagues did not adjust their results for the interval between the last menstrual period and the first measurement, inevitably the recruits with a more recent menopause will be losing faster at a time of rapidly diminishing rates of loss.14 These recent findings make it likely that the indications for screening proposed by Compston in this issue will find favour. The general principle involved is that screening should be used selectively to aid the making of genuine therapeutic decisions. By far the largest category of patients covered by this principle are women who have fairly recently passed through the menopause. This view does not differ substantially from that of a working group of the National Osteoporosis Foundation in the USA.15 For the future, studies are needed of the potentially enhanced value of screening by means of single measurements of bone density followed by identification of early vertebral fractures using lateral spinal X-rays 10-15 years after menopause. The next question to be raised is whether screening for cardiovascular risk factors might in future also be used to aid in the making of decisions on HRT use. The beneficial effects of HRT on lipoproteins16 and lipid profiles are due to its oestrogen
FUTURE PROSPECTS FOR HRT
463
component. There is some evidence that the effect of progestogens in combined preparations may offset this effect of oestrogens with beneficial effect on HDL-cholesterol concentrations being blunted.17 One recent study using low dose medroxyprogesterone in contrast found no adverse effect on lipid profiles when it was added to conjugated equine oestrogens ('Premarin').18 However, the effect on cardiovascular mortality of HRT observed in most studies19 is greater than can be accounted for by observed changes in plasma lipid profiles so some investigators have suggested that oestrogens protect the vasculature through other mechanisms.20 Unless lipid profiles act as surrogate for the other risk factors which may be abated by HRT use, it is uncertain whether they would form a valid basis for a screening test on which to base a decision on HRT use at menopause. STOPPING HRT Many women commencing HRT are greatly interested in when they can cease taking it. This is also a question of considerable financial importance. There is a dearth of knowledge concerning the effects of stopping HRT in women who have received longterm treatment. Well-controlled short-term studies have suggested that bone loss, which is minimal during long-term treatment, restarts at a rate which parallels that seen at menopause.21 It is a widely held view that HRT postpones menopause for as long as it is prescribed, so that a woman aged 80, who previously had 10 years' treatment with HRT, will have the bones she would have had at 70 if she had been untreated. That is unproven. However, Lindsay et al. published data showing that 10 years' treatment with mestranol (a synthetic oestrogen) in oophorectomized women resulted in a 25% higher bone mass in the lumbar spine and a 13% greater mass in the proximal femur than in controls.22 Rates of loss from these sites immediately after natural menopause range from 1—4% a year measured with dual photon absorptiometry and slow down with the passage of time,23 so it could take many years for such an accumulated benefit to be dissipated. ALTERNATIVES TO HRT There has been increasing interest in non-oestrogenic treatments which inhibit bone loss.24 Calcitonin, administered intranasally, prevented postmenopausal bone loss in normal women25 and
464
HORMONE REPLACEMENT THERAPY
women with Colles' fractures of the radius.26 Anabolic steroids such as nandrolone and stanozolol are also capable of impeding bone loss.27 The bisphosphonates are a group of drugs which are structurally similar to pyrophosphate but resist the action of pyrophosphatase and inhibit osteoclastic bone resorption. The first generation bisphosphonate etidronate, given intermittently, has been shown to reduce bone remodelling, to result in a small benefit in bone mass relative to controls, and appears to have a surprisingly large benefit in preventing new fractures, according to the early results of two randomized controlled trials which are continuing for a total of at least 4 years.28'29 Calcitonin is likely to remain expensive in relation to other agents for the prevention of bone loss, except in the context of painful episodes such as occur acutely after fractures, when it may be valuable.30 Anabolic steroids and bisphosphonates may ultimately prove to be useful alternatives to HRT in older women (particularly those who do not wish to experience menstruation and other side effects of HRT) as well as in men, providing future studies are able to document their long-term efficacy against fracture. Treatments which radically increase bone mass in the spine are also under investigation. However, sodium fluoride gave disappointing results in two 31 ' 32 out of three33 trials of antifracture efficacy, while no study of the antifracture efficacy of parathyroid peptides has yet been undertaken, although it may greatly increase spinal trabecular bone density.34 In contrast to its role in the treatment of osteoporosis, HRT is not yet a generally accepted form of therapy in the secondary prevention of myocardial infarction.35
FUTURE RESEARCH There are indications that the more widespread use of HRT could make a substantial impact on health, mainly through preventing fractures, myocardial infarction and stroke. Great uncertainty attends current estimates of the size of the impact HRT would have on health. Also, a programme offering HRT unselectively would be expensive and resisted by many women. In one survey, over 50% of women aged 50-52 were worried about side-effects of treatment but also about three-quarters of them were interested in taking it if osteoporosis was thereby prevented.36 About 20%
FUTURE PROSPECTS FOR HRT
465
regarded continued menstruation as an absolute contra-indication to taking HRT. At present, doctors have good reason to consider that they are poorly placed to advise their patients on the merits of starting HRT, either at the menopause or later. Substantial uncertainties remain concerning the following: the acceptability of long-term HRT which involves regular menstruation; the cardiovascular effects of combined oestrogen-gestogen preparations; the optimum duration of therapy; and the rate at which protection is lost once therapy is stopped; and finally, whether a bone mass measurement at menopause is as predictive of fracture risk as one 20 years later. Whether there is a role for a selective approach to HRT provision, either to satisfy the requirements of health providers or of patients, is controversial and depends as much or more on whether selection would be helpful in the context of circulatory as of locomotor disease. As argued by Meade and Berra (this issue), the scientific method which offers the best prospect of giving sufficiently precise answers to the above questions is the randomized controlled trial (RCT). At present a relatively small RCT is being initiated in Denmark (The Danish Osteoporosis Prevention Study, DOPS) in which 1000 women will be allocated to HRT (combined oestrogen progestogen) or no HRT just after the menopause. In the first 10 years, based on fracture rates in Rochester, Minnesota, this is expected to yield only 29 vertebral and 1 hip fracture in the control arm. Therefore, the potential of studies of this size for quantitating the preventive power of HRT lies in the first 20 years of the next century when the incidence of fractures in the cohort has risen substantially with their advancing age. To obtain earlier answers will require substantially larger studies based on considerable numbers of collaborating primary care physicians similar to those organized in the MRC GP research framework. The indications are that there is sufficient interest among primary care physicians for such a study to be successfully organized.4 HRT IN THE NEXT CENTURY At present there is a window of opportunity to study scientifically important questions concerning the role of HRT in protecting women's health. With strong lay and medical opinions already forming, there is a possibility that without randomized trials of the effectiveness of HRT in primary and secondary prevention,
466
HORMONE REPLACEMENT THERAPY
and the role of screening in selecting for HRT, a new clinical orthodoxy will develop based on lay perceptions interacting with over-interpreted case-control data. The prospects seem promising for eventually meeting women's concerns about the need for regular menstruation as protection against carcinoma of the uterine body. Gallagher et al.18 have administered low dose conjugated equine oestrogen (0.3ng/day) with low dose medroxyprogesterone to volunteers who were up to 6 years postmenopause at the start of the study. Spinal and peripheral bone was conserved comparably to bone in a group treated with twice the dose of oestrogen given alone. However, a third group given medroxyprogesterone alone lost spinal bone. These workers sought an explanation for their findings in the ability of oestrogens to promote the synthesis of progestogen receptors in human bone cells.37 Christiansen and Riis17 have treated women with osteoporosis with continuous oestradiol and norethisterone for 1 year. Excellent results were obtained in conserving axial and peripheral bone. It remains to be determined whether these and other combined hormone regimes provide similar degrees of cardiovascular protection to oestrogen given alone. Although the secular upward trend in hip fracture incidence appears to be slowing in Britain,38 as elsewhere, it seems unlikely that female fracture rates will better those of men even if all women in future receive HRT long-term. This will still leave, for example, half of female fractures of the proximal femur unaccounted for. The true causes of the poor and declining skeletal health of women in westernized industrial countries must be further investigated to see if environmental determinants of fracture risk can be identified which can be ameliorated or abolished by suitable public health measures. REFERENCES 1 Solomon L, Bone density in ageing Caucasian and African populations. Lancet 1979; ii: 1325-1330 2 Law MR, Wald NJ, Meade TW. Strategics for prevention of osteoporosis and hip fracture. Br Med J 1991; 303: 453-459 3 Grimley Evans J. The significance of osteoporosis. In: Smith R ed. Osteoporosis 1990. London: Royal College of Physicians, 1990: pp. 1-8 4 Wilkes HC, Meade TW. Hormone replacement therapy in general practice: a survey of doctors in the MRC's general practice research framework. Br Med J 1991; 302: 1317-1320 5 Robine JM, Ritchie K. Healthy life expectancy: evaluation of global indicator of change in population health. Br Med J 1991; 302: 457-460
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6 Todd C, Williams R, Pryor G, Parker M, Myles J. Early discharge to 'hospital at home' after fracture of neck of femur: psychosocial factors. In: Brenner G, Weber I, eds. Health services research and primary health care CProccedings of 2nd European Conference). Koln: Deutsche Arzte-Verlag, 1991: pp. 185-189 7 Roche M, Vessey M. Hormone replacement therapy in the menopause: risks, benefits and costs. In: Smith R. ed. Osteoporosis 1990. London: Royal College of Physicians, 1990: pp. 189-198. (erratum) 8 Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991; 114: 919-923 9 Ross PD, Davis JW, Vogel JM, Wasnich RD. A critical review of bone mass and the risk of fractures in osteoporosis. Calcif Tiss Int 1990; 46: 149-161 10 Cummings SR, Black DM, Nevitt MC et al. Appendicular bone density and age predict hip fracture in women. J Am Med Assoc 1990; 263: 665-668 11 Cooper C, Atkinson E, O'Fallon WM, Riggs BL, Melton LJ III. The epidemiology of vertebral fractures in Rochester, Minnesota. J Bone Min Res 1991; 6 (suppl 1): S300 (abstract) 12 Hui SL, Slemenda CW, Johnston CC Jr. The contribution of bone loss to postmenopausal osteoporosis. Osteoporosis Int 1990; 1: 30-34 13 Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss. Br Med J 1991; 303: 961-964 14 Prince RL, Smith M, Dick IM, Price RI, Webb PG, Henderson NK, Harris MM. Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation and hormone replacement therapy. N Engl J Med 1991; 325: 1189-1195 15 Report from the Scientific Advisory Board of the National Osteoporosis Foundation. Raisz LG, ed. J Bone Min Res 1989; 4 (suppl 2): Sl-28 16 Walsh BW, SchifT I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196-1204 17 Christiansen C, Riis BJ. 17|3-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J Clin Endocrinol Metab 1990; 71: 836-841 18 Gallagher JC, Kable WT, Goldgar D. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991; 90: 171-178 19 Bush TL, Barrett-Connor E, Cowan LD et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102-1109 20 Samsioe G, Mattsson LA. Effects of estrogens and progestogens on lipid metabolism. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp. 1806-1816 21 Christiansen C, Christensen MS, Transbol IB. Bone mass in postmenopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet 1981; i: 459^161 22 Lindsay R, Hart DM, Abdalla H, Al-Azzawu F. Inter-relationship of bone loss and its prevention, and fracture expression. In: Osteoporosis 1987. eds. Christiansen C, Johansen JS, Riis BJ. Copenhagen: Osteopress ApS, 1987: pp.508-512 23 Reeve J, Green JR, Hesp R et al. Determinants of axial bone loss in the early postmenopause: The Harrow post menopausal bone loss study. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp.101-103 24 Reeve J. Restoring trabecular bone mass in established osteoporosis. In: Smith R, ed. Osteoporosis 1990. London: The Royal College of Physicians, 1990: pp.143-155 25 Reginster YJ, Albert A, Lecart MP et al. One year controlled randomised trial
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26 27
28
29 30 31 32 33 34 35 36 37 38
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of prevention of early post-menopausal bone loss by intranasal calcitonin. Lancet 1987; ii: 1481-1483 Overgaard K, Riis BJ, Christiansen C et al. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30: 435-442 Guesens P, Dequeker J. Long-term effect of nandrolone decanoate, l6hydroxyvitamin D 3 or intermittent calcium infusion therapy on bone mineral content, bone remodelling and fracture rate in symptomatic osteoporosis: a double-blind controlled study. J Bone Min Res 1986; 1: 346-357 Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 12651271 Watts NB, Harris ST, Genant HK et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73-79 Gennari C. The analgesic activity of intranasal salmon calcitonin in the osteoporotic patient. New findings. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp. 1872-1887 Riggs BL, Hodgson SF, O'Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-809 Kleerekoper M, Peterson EL, Nelson DA et al. A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporosis Int 1991; 1: 155-161 Mamellc N, Meunier PJ, Dusan R, et al. Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 1988; ii: 361-365 Reeve J, Davies UM, Hesp R, McNally E, Katz D. Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride. Br Med J 1990; 301: 314-318 Beaglehole R. Oestrogens and cardiovascular disease. Br Med J 1988; 297: 571-572 Draper J, Roland M. Perimenopausal women's views on taking hormone replacement therapy to prevent osteoporosis. Br Med J 1990; 300: 786-788 Benz DJ, Haussler MR, Komm BS. Estrogen binding and cstrogenic responses in normal human osteoblast-like cells. J Bone Min Res 1991; 6: 531-541 Spector TD, Cooper C, Fenton Lewis A. Trends in admission for hip fracture in England and Wales 1968-85. Br Med J 1990; 300: 1173-1174
Future prospects for hormone replacement therapy J Reeve MRC Clinical Research Centre, Harrow, UK
To avoid the complication of osteoporosis, hormone replacement therapy (HRT) is now standard therapy in women with premature ovarian failure. The indications for HRT after the age of 50 are more controversial. There are strong indications from case-control studies that in N. America and Europe HRT protects against osteoporotic fracture, myocardial infarction and stroke; yet the evidence from case control studies is insufficiently precise to quantitate accurately the potential benefits that would accrue from its more widespread use. Clear guidelines also need to be established on the potential usefulness of selective prescribing of HRT using one or more screening procedures. The only effective way of achieving this and of quantitating the potential benefits of HRT with sufficient accuracy is by means of one or more randomized controlled trials. Future research will also address concerns such as the possible increase in the risk of breast cancer after 10 or more years of therapy. Critical to the more widespread acceptance of HRT may be the development of safe regimes which do not promote uterine bleeding as well as minimizing other unwanted side-effects.
It will be clear from reading the other contributions to diis number of the Bulletin that many scientific issues of substance remain to be resolved before the practising doctor can judge straightforwardly when to prescribe HRT and for how long. In many cases, the decision will be heavily influenced by the personal preference of the individual patient, who will make a choice based on the medical advice received. This will be weighed against the good
FUTURE PROSPECTS FOR HRT
459
and bad effects of HRT as she sees or experiences them. In this paper an attempt is made to identify the preconditions for a rational strategy for HRT use in a wider primary care and public health framework. WHY SHOULD HRT BE NECESSARY? The principal adverse consequences of menopause relate to its effects on the cardiovascular system and the skeleton as well as on the urogenital tract and subjective well-being, including cerebral function. However, with regard to the cardiovascular system and the skeleton, evidence that menopause leads to significant adverse health consequences comes largely from studies on affluent, westernized populations. Whereas postmenopausal bone loss appears to occur at similar rates in African as in European populations, there is evidence that age-adjusted rates of serious insufficiency fractures are at least an order of magnitude lower in some African populations.1 Likewise, cardiovascular disease secondary to atherosclerosis occurs at much lower rates in many third world than in typical western postmenopausal populations. Oriental populations also have lower rates. The secular trends in both osteoporotic fractures and myocardial disease evident over the last three decades in most western countries point to important environmental influences on these disorders which, at least until recently, have been growing increasingly adverse. These have little to do with the hormonal status of the women affected since age at menopause has changed almost imperceptibly in the last 100 years. Nor can simple clinical measurements, such as cholesterol levels or bone density indices, be used as measures of risk that can, for example, be transferred from an affluent western population to a third world population. A rational policy for combatting heart disease or osteoporosis will have to take into account local population characteristics, degrees of risk and, where appropriate, the local usefulness of clinical measurements in selecting women at particular risk. Accordingly, HRT is more likely to promote women's health in affluent westernized cultures than in third world subsistence cultures. The reasons why this should be so are profoundly interesting but are far from being understood. Inevitably, the reasons for the relatively poor, and recently worsening, skeletal and cardiovascular health of postmenopausal women in western cultures have been sought in their changing diets, exercise habits and consumption
460
HORMONE REPLACEMENT THERAPY
of tobacco. In Britain, energy consumption has fallen by an average of 18% in 2 decades,2 indicating reduced levels of physical activity. Smoking rates in women peaked after those in men;3 while diets have altered towards patterns adding to the risk of cardiovascular disease. THE CASE FOR SELECTIVITY An impressive finding of the survey among primary care physicians reported by Wilkes and Meade4 was the perceived need for guidance from further research on the risks and benefits of HRT. While about 60% of doctors would at present contemplate using HRT for prevention of cardiovascular disease or osteoporosis, they appeared to be prescribing selectively and only 7 to 10% of eligible women were receiving treatment. Whereas the personal preferences of women undoubtedly play a large part in the decision to treat, many wish to make their choice conditional on the balance of risks and benefits. Concern among patients about the relative risks of diseases such as osteoporosis, heart disease and breast cancer, which may be modified by HRT, may not accord with the prevalence of these diseases or with the death rates which are attributable to them. This is natural in view of the different degrees of suffering caused by each. Apart from this, many women are more concerned at age 50 about health issues in their sixth and seventh decades than in the diseases perceived to be of old age, such as hip fracture. In line with this, they regard postponement of an adverse effect, such as a myocardial infarct or fracture, as valuable particularly if it postpones long-term ill health or dependency. In general, most women at the age of menopause are seeking to optimize their healthy (disability-free) life expectancy (DFLE) rather than their total life expectancy. As Robine and Ritchie* have shown, this is only about 80% of total life expectancy in British women who on average, at age 50, can expect no more than 12-15 more years of DFLE. Locomotor disorders rank first and circulatory diseases second in the list of disease categories which circumscribe DFLE. The interests of agencies which fund health care may be rather different. Obviously, funding agencies are more concerned about costs of treatment than are insured patients. Besides that there is another point. A younger patient, for example, with a hip fracture may be cheaper to treat than an older one because the former is
FUTURE PROSPECTS FOR HRT
461
more likely to be suitable for an early discharge scheme.6 However, in view of the substantial costs7 of a policy of non-selective assignment to HRT, both patients and funding agencies have a considerable interest in the possibility of prescribing HRT selectively. SCREENING: FOR AND AGAINST It has been argued that screening for any sort of index of bone quantity is an inappropriate use of resources because of the poor selectivity of bone densitometry for women at risk of fracture.2 A recent study, however, has revealed that very much better estimates of vertebral fracture risk are obtainable than was previously thought possible,8 which makes it necessary to re-examine the question. Ross et al.9 collated a large number of studies estimating fracture rates in relation to bone density indices. Because of potential sources of bias the most valid data are likely to be prospective studies which have adjusted for age. The largest study examining hip fracture rates estimated that the relative risk of hip fracture for a 1 S.D. reduction in peripheral bone density, used as the sole measure of risk, ranged from 1.41 to 1.66 according to measurement site.10 Age was an independent predictor of hip fracture in this study, the risk doubling with each additional decade of age. For vertebral fractures a similar, rather stronger, relationship between bone mass and peripheral bone density indices was obtained by Ross et al.8 However, they also found that the existence of previous vertebral fractures was an additional, powerful predictor of further fractures. Relative to a woman with no spinal fractures in the highest tertile for calcaneal bone mass, a woman in the lowest tertile had a seven-fold increase in risk of a new fracture, but a 25-fold increase in risk if she had previously had a vertebral fracture. This was after adjusting for age, although age was no longer a statistically significant determinant of fracture risk when both bone mass and pre-study fracture prevalence were included in the model. In view of the relatively high prevalence of vertebral fractures from the 7th decade on, a spinal X-ray might be a practical additional means of assessing risk. Therefore, the means for identifying reasonably precisely the women at risk of a second or subsequent vertebral fracture based on two simple low dose radiological procedures may be available. A recent study by Cooper et al.11 suggests that about half of all patients suffering a vertebral fracture in Rochester, Minnesota, do
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not present for investigation and could only be identified by routine screening. This accords with other data suggesting that vertebral fractures have a long-term impact on health which depends substantially on how many vertebrae have been damaged. So an X-ray would have to be asked for with screening in mind in some cases. An argument that has been raised against screening using densitometry is that bone loss after the time of measurement may differ substantially between individuals. In the later post-menopause Hui et al. have found that rates of bone loss vary considerably and bear little relation to measurements of loss in the same individuals made in the early postmenopausal period.12 Nevertheless Hansen et al. in another long-term prospective study have suggested that women who lose bone more rapidly than average from the forearm can be predicted to have cumulatively lost more than their peers some 12 years after the menopause.13 This is to some extent the result of the fairly dramatic slowing of forearm bone loss; with the passage of time after menopause Hansen and colleagues found that about half the total loss occurs in the first 2-3 years. However, Hansen's suggestions13 that biochemical measurements may be used to predict the fast loser may be an example of biochemical 'overkill'. Since Hansen and colleagues did not adjust their results for the interval between the last menstrual period and the first measurement, inevitably the recruits with a more recent menopause will be losing faster at a time of rapidly diminishing rates of loss.14 These recent findings make it likely that the indications for screening proposed by Compston in this issue will find favour. The general principle involved is that screening should be used selectively to aid the making of genuine therapeutic decisions. By far the largest category of patients covered by this principle are women who have fairly recently passed through the menopause. This view does not differ substantially from that of a working group of the National Osteoporosis Foundation in the USA.15 For the future, studies are needed of the potentially enhanced value of screening by means of single measurements of bone density followed by identification of early vertebral fractures using lateral spinal X-rays 10-15 years after menopause. The next question to be raised is whether screening for cardiovascular risk factors might in future also be used to aid in the making of decisions on HRT use. The beneficial effects of HRT on lipoproteins16 and lipid profiles are due to its oestrogen
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component. There is some evidence that the effect of progestogens in combined preparations may offset this effect of oestrogens with beneficial effect on HDL-cholesterol concentrations being blunted.17 One recent study using low dose medroxyprogesterone in contrast found no adverse effect on lipid profiles when it was added to conjugated equine oestrogens ('Premarin').18 However, the effect on cardiovascular mortality of HRT observed in most studies19 is greater than can be accounted for by observed changes in plasma lipid profiles so some investigators have suggested that oestrogens protect the vasculature through other mechanisms.20 Unless lipid profiles act as surrogate for the other risk factors which may be abated by HRT use, it is uncertain whether they would form a valid basis for a screening test on which to base a decision on HRT use at menopause. STOPPING HRT Many women commencing HRT are greatly interested in when they can cease taking it. This is also a question of considerable financial importance. There is a dearth of knowledge concerning the effects of stopping HRT in women who have received longterm treatment. Well-controlled short-term studies have suggested that bone loss, which is minimal during long-term treatment, restarts at a rate which parallels that seen at menopause.21 It is a widely held view that HRT postpones menopause for as long as it is prescribed, so that a woman aged 80, who previously had 10 years' treatment with HRT, will have the bones she would have had at 70 if she had been untreated. That is unproven. However, Lindsay et al. published data showing that 10 years' treatment with mestranol (a synthetic oestrogen) in oophorectomized women resulted in a 25% higher bone mass in the lumbar spine and a 13% greater mass in the proximal femur than in controls.22 Rates of loss from these sites immediately after natural menopause range from 1—4% a year measured with dual photon absorptiometry and slow down with the passage of time,23 so it could take many years for such an accumulated benefit to be dissipated. ALTERNATIVES TO HRT There has been increasing interest in non-oestrogenic treatments which inhibit bone loss.24 Calcitonin, administered intranasally, prevented postmenopausal bone loss in normal women25 and
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women with Colles' fractures of the radius.26 Anabolic steroids such as nandrolone and stanozolol are also capable of impeding bone loss.27 The bisphosphonates are a group of drugs which are structurally similar to pyrophosphate but resist the action of pyrophosphatase and inhibit osteoclastic bone resorption. The first generation bisphosphonate etidronate, given intermittently, has been shown to reduce bone remodelling, to result in a small benefit in bone mass relative to controls, and appears to have a surprisingly large benefit in preventing new fractures, according to the early results of two randomized controlled trials which are continuing for a total of at least 4 years.28'29 Calcitonin is likely to remain expensive in relation to other agents for the prevention of bone loss, except in the context of painful episodes such as occur acutely after fractures, when it may be valuable.30 Anabolic steroids and bisphosphonates may ultimately prove to be useful alternatives to HRT in older women (particularly those who do not wish to experience menstruation and other side effects of HRT) as well as in men, providing future studies are able to document their long-term efficacy against fracture. Treatments which radically increase bone mass in the spine are also under investigation. However, sodium fluoride gave disappointing results in two 31 ' 32 out of three33 trials of antifracture efficacy, while no study of the antifracture efficacy of parathyroid peptides has yet been undertaken, although it may greatly increase spinal trabecular bone density.34 In contrast to its role in the treatment of osteoporosis, HRT is not yet a generally accepted form of therapy in the secondary prevention of myocardial infarction.35
FUTURE RESEARCH There are indications that the more widespread use of HRT could make a substantial impact on health, mainly through preventing fractures, myocardial infarction and stroke. Great uncertainty attends current estimates of the size of the impact HRT would have on health. Also, a programme offering HRT unselectively would be expensive and resisted by many women. In one survey, over 50% of women aged 50-52 were worried about side-effects of treatment but also about three-quarters of them were interested in taking it if osteoporosis was thereby prevented.36 About 20%
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regarded continued menstruation as an absolute contra-indication to taking HRT. At present, doctors have good reason to consider that they are poorly placed to advise their patients on the merits of starting HRT, either at the menopause or later. Substantial uncertainties remain concerning the following: the acceptability of long-term HRT which involves regular menstruation; the cardiovascular effects of combined oestrogen-gestogen preparations; the optimum duration of therapy; and the rate at which protection is lost once therapy is stopped; and finally, whether a bone mass measurement at menopause is as predictive of fracture risk as one 20 years later. Whether there is a role for a selective approach to HRT provision, either to satisfy the requirements of health providers or of patients, is controversial and depends as much or more on whether selection would be helpful in the context of circulatory as of locomotor disease. As argued by Meade and Berra (this issue), the scientific method which offers the best prospect of giving sufficiently precise answers to the above questions is the randomized controlled trial (RCT). At present a relatively small RCT is being initiated in Denmark (The Danish Osteoporosis Prevention Study, DOPS) in which 1000 women will be allocated to HRT (combined oestrogen progestogen) or no HRT just after the menopause. In the first 10 years, based on fracture rates in Rochester, Minnesota, this is expected to yield only 29 vertebral and 1 hip fracture in the control arm. Therefore, the potential of studies of this size for quantitating the preventive power of HRT lies in the first 20 years of the next century when the incidence of fractures in the cohort has risen substantially with their advancing age. To obtain earlier answers will require substantially larger studies based on considerable numbers of collaborating primary care physicians similar to those organized in the MRC GP research framework. The indications are that there is sufficient interest among primary care physicians for such a study to be successfully organized.4 HRT IN THE NEXT CENTURY At present there is a window of opportunity to study scientifically important questions concerning the role of HRT in protecting women's health. With strong lay and medical opinions already forming, there is a possibility that without randomized trials of the effectiveness of HRT in primary and secondary prevention,
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and the role of screening in selecting for HRT, a new clinical orthodoxy will develop based on lay perceptions interacting with over-interpreted case-control data. The prospects seem promising for eventually meeting women's concerns about the need for regular menstruation as protection against carcinoma of the uterine body. Gallagher et al.18 have administered low dose conjugated equine oestrogen (0.3ng/day) with low dose medroxyprogesterone to volunteers who were up to 6 years postmenopause at the start of the study. Spinal and peripheral bone was conserved comparably to bone in a group treated with twice the dose of oestrogen given alone. However, a third group given medroxyprogesterone alone lost spinal bone. These workers sought an explanation for their findings in the ability of oestrogens to promote the synthesis of progestogen receptors in human bone cells.37 Christiansen and Riis17 have treated women with osteoporosis with continuous oestradiol and norethisterone for 1 year. Excellent results were obtained in conserving axial and peripheral bone. It remains to be determined whether these and other combined hormone regimes provide similar degrees of cardiovascular protection to oestrogen given alone. Although the secular upward trend in hip fracture incidence appears to be slowing in Britain,38 as elsewhere, it seems unlikely that female fracture rates will better those of men even if all women in future receive HRT long-term. This will still leave, for example, half of female fractures of the proximal femur unaccounted for. The true causes of the poor and declining skeletal health of women in westernized industrial countries must be further investigated to see if environmental determinants of fracture risk can be identified which can be ameliorated or abolished by suitable public health measures. REFERENCES 1 Solomon L, Bone density in ageing Caucasian and African populations. Lancet 1979; ii: 1325-1330 2 Law MR, Wald NJ, Meade TW. Strategics for prevention of osteoporosis and hip fracture. Br Med J 1991; 303: 453-459 3 Grimley Evans J. The significance of osteoporosis. In: Smith R ed. Osteoporosis 1990. London: Royal College of Physicians, 1990: pp. 1-8 4 Wilkes HC, Meade TW. Hormone replacement therapy in general practice: a survey of doctors in the MRC's general practice research framework. Br Med J 1991; 302: 1317-1320 5 Robine JM, Ritchie K. Healthy life expectancy: evaluation of global indicator of change in population health. Br Med J 1991; 302: 457-460
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6 Todd C, Williams R, Pryor G, Parker M, Myles J. Early discharge to 'hospital at home' after fracture of neck of femur: psychosocial factors. In: Brenner G, Weber I, eds. Health services research and primary health care CProccedings of 2nd European Conference). Koln: Deutsche Arzte-Verlag, 1991: pp. 185-189 7 Roche M, Vessey M. Hormone replacement therapy in the menopause: risks, benefits and costs. In: Smith R. ed. Osteoporosis 1990. London: Royal College of Physicians, 1990: pp. 189-198. (erratum) 8 Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existing fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991; 114: 919-923 9 Ross PD, Davis JW, Vogel JM, Wasnich RD. A critical review of bone mass and the risk of fractures in osteoporosis. Calcif Tiss Int 1990; 46: 149-161 10 Cummings SR, Black DM, Nevitt MC et al. Appendicular bone density and age predict hip fracture in women. J Am Med Assoc 1990; 263: 665-668 11 Cooper C, Atkinson E, O'Fallon WM, Riggs BL, Melton LJ III. The epidemiology of vertebral fractures in Rochester, Minnesota. J Bone Min Res 1991; 6 (suppl 1): S300 (abstract) 12 Hui SL, Slemenda CW, Johnston CC Jr. The contribution of bone loss to postmenopausal osteoporosis. Osteoporosis Int 1990; 1: 30-34 13 Hansen MA, Overgaard K, Riis BJ, Christiansen C. Role of peak bone mass and bone loss. Br Med J 1991; 303: 961-964 14 Prince RL, Smith M, Dick IM, Price RI, Webb PG, Henderson NK, Harris MM. Prevention of postmenopausal osteoporosis. A comparative study of exercise, calcium supplementation and hormone replacement therapy. N Engl J Med 1991; 325: 1189-1195 15 Report from the Scientific Advisory Board of the National Osteoporosis Foundation. Raisz LG, ed. J Bone Min Res 1989; 4 (suppl 2): Sl-28 16 Walsh BW, SchifT I, Rosner B, Greenberg L, Ravnikar V, Sacks FM. Effects of postmenopausal estrogen replacement on the concentrations and metabolism of plasma lipoproteins. N Engl J Med 1991; 325: 1196-1204 17 Christiansen C, Riis BJ. 17|3-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women. J Clin Endocrinol Metab 1990; 71: 836-841 18 Gallagher JC, Kable WT, Goldgar D. Effect of progestin therapy on cortical and trabecular bone: comparison with estrogen. Am J Med 1991; 90: 171-178 19 Bush TL, Barrett-Connor E, Cowan LD et al. Cardiovascular mortality and noncontraceptive use of estrogen in women: results from the Lipid Research Clinics Program Follow-up Study. Circulation 1987; 75: 1102-1109 20 Samsioe G, Mattsson LA. Effects of estrogens and progestogens on lipid metabolism. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp. 1806-1816 21 Christiansen C, Christensen MS, Transbol IB. Bone mass in postmenopausal women after withdrawal of oestrogen/gestagen replacement therapy. Lancet 1981; i: 459^161 22 Lindsay R, Hart DM, Abdalla H, Al-Azzawu F. Inter-relationship of bone loss and its prevention, and fracture expression. In: Osteoporosis 1987. eds. Christiansen C, Johansen JS, Riis BJ. Copenhagen: Osteopress ApS, 1987: pp.508-512 23 Reeve J, Green JR, Hesp R et al. Determinants of axial bone loss in the early postmenopause: The Harrow post menopausal bone loss study. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp.101-103 24 Reeve J. Restoring trabecular bone mass in established osteoporosis. In: Smith R, ed. Osteoporosis 1990. London: The Royal College of Physicians, 1990: pp.143-155 25 Reginster YJ, Albert A, Lecart MP et al. One year controlled randomised trial
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of prevention of early post-menopausal bone loss by intranasal calcitonin. Lancet 1987; ii: 1481-1483 Overgaard K, Riis BJ, Christiansen C et al. Nasal calcitonin for treatment of established osteoporosis. Clin Endocrinol 1989; 30: 435-442 Guesens P, Dequeker J. Long-term effect of nandrolone decanoate, l6hydroxyvitamin D 3 or intermittent calcium infusion therapy on bone mineral content, bone remodelling and fracture rate in symptomatic osteoporosis: a double-blind controlled study. J Bone Min Res 1986; 1: 346-357 Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH. Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 1990; 322: 12651271 Watts NB, Harris ST, Genant HK et al. Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 1990; 323: 73-79 Gennari C. The analgesic activity of intranasal salmon calcitonin in the osteoporotic patient. New findings. In: Christiansen C, Overgaard K, eds. Osteoporosis 1990. Copenhagen: Osteopress ApS, 1990: pp. 1872-1887 Riggs BL, Hodgson SF, O'Fallon WM, et al. Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990; 322: 802-809 Kleerekoper M, Peterson EL, Nelson DA et al. A randomized trial of sodium fluoride as a treatment for postmenopausal osteoporosis. Osteoporosis Int 1991; 1: 155-161 Mamellc N, Meunier PJ, Dusan R, et al. Risk-benefit ratio of sodium fluoride treatment in primary vertebral osteoporosis. Lancet 1988; ii: 361-365 Reeve J, Davies UM, Hesp R, McNally E, Katz D. Treatment of osteoporosis with human parathyroid peptide and observations on effect of sodium fluoride. Br Med J 1990; 301: 314-318 Beaglehole R. Oestrogens and cardiovascular disease. Br Med J 1988; 297: 571-572 Draper J, Roland M. Perimenopausal women's views on taking hormone replacement therapy to prevent osteoporosis. Br Med J 1990; 300: 786-788 Benz DJ, Haussler MR, Komm BS. Estrogen binding and cstrogenic responses in normal human osteoblast-like cells. J Bone Min Res 1991; 6: 531-541 Spector TD, Cooper C, Fenton Lewis A. Trends in admission for hip fracture in England and Wales 1968-85. Br Med J 1990; 300: 1173-1174
