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ANDROPAUSE Prophylaxis of with 235

PROPHYLAXIS OF OSTEOPOROSIS WITH ESTROGENS

M. H. BIRKHÄUSER

the later postmenopausal fracture risk INTRODUCTION depends largely on the mass present at the time of the menopause.

In the early forties, Albright [1] clearly identified the connection between estrogens and bone mineral content, OSTEOPOROSIS RISK AND and showed that bone is -dependent. However, it took ESTROGEN EFFECTS IN THE BONE: another 30 years for this pathophysio­ COMMON CONSIDERATIONS logical concept to prevail in clinical practice. Today it is generally accepted that any form of ovarian insufficiency Peak bone mass is determined indi­ with an estrogen deficiency exceeding vidually, on the one hand by genetic six months results in a metabolic shift factors, and on the other hand by the in bone metabolism that increases production of sexual during bone turnover. The destruction of bone the important years of adolescence and mass predominates over bone forma­ by lifestyle [2, 3]. Africans, for exam­ tion, which leads to a massive increase ple, have a higher bone mass on aver­ in the risk of a clinically relevant loss of age than Europeans or Asians. Since a , and subsequently to an woman’s peak bone mass is acquired increase in fracture risk. in adolescence, especially between the The principle of hormonal prophy­ age of 11 and 18 years, and since the laxis for osteoporosis was introduced possibility of a further, limited increase some thirty years ago. Initially, only in bone mass ends with the age of 30 at estrogens were administered, which is the latest, a normal endocrine milieu only permissible in women with hyster­ and thus normal estrogen production ectomy. Today, hormone replacement with regular cycles in adolescence is with a combination of estrogen and just as important as a healthy diet and progestagen is routine in women with sensible life-style [4–6]. Once the peak an intact uterus in . As a princi­ bone mass has been reached, the ple, not only older women with an in­ annual bone loss rate until the meno- creased risk of osteoporosis, but also pause is approx. 0.7%, then it rises to every younger woman with amenor­ 5% in the trabecular bone and to 1– rhea of more than six months duration 1.5% in the whole skeleton for several should receive estrogen replacement. years, and finally it normally drops to The omission of replacement therapy in the age-related loss rate again. After the a premenopausal woman with amenor­ menopause, bone loss is highest in fair­ rhea is now regarded as a mistake, since skinned European or Asian, thin and 236 Prophylaxis of Osteoporosis with Estrogens physically inactive women, and lowest Estrogens probably improve in African women [7, 8]. In heavy absorption via 1,25-dihydroxy-vitamin smokers, the risk of a femoral neck D [21]. This process is not age-related. fracture is increased by 40–45% [9]. The protective effect of estrogen on the The decisive factors are sufficient cal­ bone is proportional to the serum level cium intake (in the postmenopause of endogen and pro­ 1500 mg/day without HRT and 1000– duction [22] respectively to the admin­ 1200 mg/day with HRT), and sufficient istered estrogen dose [23–25]. Unfortu­ intake and activation of [10]. nately, it is still not known well enough Regular exercise improves bone den­ that estrogen deficiency in young sity [11–14]. The unfavourable effect of women with primary or secondary treatment with can be can cause severe loss of diminished by hormone replacement bone substance even after a fairly short therapy (HRT) [15, 16]. duration [26]. Contrary to common assumption, there is no correlation between the severity of subjective climacteric symp­ toms and the decrease of bone mass in the spine and femoral neck [17, 18]. INFLUENCE OF ESTROGEN ADMINI­ However, there is a certain correlation between the baseline values for bone STRATION ON FRACTURE RATE density on the one hand and age at the time of menarche on the other hand. In addition to the numerous investiga­ This correlation is significant for the tions of osteoporosis prevention with femoral neck. Late menarche usually estrogens and progestagens, in which implies reduced bone density. A high surrogate parameters such as bone body mass index results in better bone density or biochemical bone parameters mass, partly via increased acyclical, were measured, there are also studies peripheral aromatized estrogens, partly on the fracture rate during HRT, show­ via mechanical factors (greater burden ing that HRT offers significant protection on the bone!) [19]. However, it is in­ against osteoporotic bone fractures correct to assume that obese women in [27, 28]. However, this requires that general do not have an increased osteo­ the treatment should be continued for porosis risk after the menopause. several years. The minimum duration Estrogens reduce primarily the ac­ of treatment appears to be five years, celerated bone absorption and only according to other opinions it is closer secondly the bone destruction. This to ten years. An insufficient duration of results in a transient positive bone bal­ HRT administration or merely local ance. Thus, the bone density increases administration of estrogens, e.g. for the in the first phase of estrogen adminis­ treatment of subjective symptoms dur­ tration, but the effect flattens with on­ ing the first years after the menopause, going HRT. Estrogens presumably do not guarantee long-term protection modulate the bone metabolism by in­ against osteoporotic fractures. Cohort hibiting the osteoclast activity through studies have shown that long-term HRT various local autocrine and paracrine reduces the incidence of spinal defor­ factors [20]. Estrogen deficiency leads mations in the postmenopause by to the predominance of osteoclast ac­ about 90% [29]. Other data show tivity with increased bone destruction. that HRT reduces the risk of radius and Prophylaxis of Osteoporosis with Estrogens 237 femoral neck fractures by about half over a period of at least six years. INFLUENCE OF THE PROGESTAGEN In order to obtain optimal compli­ ance, the form of administration of the COMPONENT hormonal osteoporosis prophylaxis must be determined individually according The extent to which the progestagen to the needs and preferences of each component is actively involved in osteo­ woman. It is essential to achieve opti­ porosis prevention has only been partly mal acceptance if we want to provide explored [30]. Progestagens definitely long-term prophylaxis over several do not counteract the osteoprotective years. The basic principles of each hor­ effects of estrogen [30]. In fact, it would mone replacement therapy are shown seem that some progestagens, such as in Table 1. Contrary to the still com­ acetate (NETA) and mon practice in the United Stated, the hexanoate, actually have their administration of estrogen alone with­ own osteoprotective activity [30–32], out gestagen in women with an intact whilst acetate uterus is contraindicated in Europe. (MPA) alone does not have any osteo­ protective effect. The osteoprotective action of NETA has also been con­ firmed in postmenopausal women who received NETA as an add-back therapy during GnRH treatment for endo­ Table 1. Hormone replacement with estrogens metriosis [33]. In the GnRH mono­ and gestagens after the menopause: Basic prin­ therapy group, bone loss occurred after ciples 6 months and was prevented by co­ administration of NETA. 1. Choice of estrogen: ● Conjugated (“natural”) equine estrogens ● 17-beta estradiol Alternatives: ● PREVENTION IN THE FERTILE PHASE, ● SERMs ● Oral hormonal contraceptives: only in the THE PERIMENOPAUSE, AND perimenopause, only for non-smokers with­ out cardiovascular risk factors THE EARLY POSTMENOPAUSE 2. Choice of galenic form: ● Oral ● (percutaneous) Regardless of the cause and the age of ● Intramuscular the patient, any hypothalamic estrogen ● Intranasal deficiency can lead to clinically rel­ ● (Vaginal, e. g. vaginal ring) ● (Implants) evant disorders of bone and lipid me­ tabolism. Whilst normal physical activ­ 3. Progestagens: Co-administration of a progestagen with a ity and healthy diet can improve bone classical estrogen is imperative, in order to mineral content in pre- and postmeno­ ● avoid the increased risk of endometrial car­ pausal women, estrogen deficiency in cinoma with estrogen monotherapy, top athletes with secondary amenor­ ● support the bone-protective effect of estrogen, depending on the progestagen (does not apply rhea and in rare cases primary amenor­ to all gestagens, see text). rhea in young girls due to a shift in 4. Individual adjustment of the therapy regime menarche can lead to an inadequate formation of the peak bone mass and 238 Prophylaxis of Osteoporosis with Estrogens thus to a markedly reduced bone den­ and the fracture incidence increases sity [34]. The same applies to women [39]. The critical threshold for bone with anorexia nervosa or bulimia, and fractures after inadequate trauma is first to those with hypothalamic amenor­ reached in the spine. A few years later rhea with other causes. the increased incidence of femoral The loss of bone mineral content neck fractures follows [40–42]. Like correlates with the duration of natural, timely menopause, premeno­ amenorrhea and the body weight, re­ pausal bilateral castration leads to a gardless of the cause. Even in young decrease in bone mass that follows women with amenorrhea aged bet­ precisely the same pathophysiological ween 18 and 25 years, bone densities rules and has the same clinical conse­ as in women aged 50–70 years can be quences with regard to osteoporosis found [26]. risk as the estrogen deficiency after Although designer estrogens may natural menopause. Less well known is also offer protection against osteoporo­ the fact that bilateral castration in the sis, as is achieved with the classic oral first years after the menopause will ac­ hormonal contraceptives in the peri­ celerate the bone loss, since the re­ menopause, natural estrogens should sidual secretion by the ovaries, be used whenever contraception is not especially of ovarian , is an issue. Every young woman with eliminated as a result [43]. The ovary is amenorrhea must receive hormone re­ not the inactive and useless organ that placement with an estrogen-progesta­ it is sometimes thought to be after the gen combination. If contraception is menopause; instead, it continues to also required, a modern low-dose birth­ have a major endocrine physiological control pill can be selected instead of function [43–45]. the usual substitution. In adolescence, Bone loss of 0.5 to 1% per year may the protective effect must however be still be regarded as physiological and monitored [35]. as a consequence of ageing [46–48], Once the peak bone mass has been but a loss of 3% or more per year is reached, the bone density remains vir­ definitely pathological: This is a clear tually unchanged until the onset of indication for hormone replacement menopause. With normal nutrition, the [30]. The most reliable and now most calcium balance is usually good and commonly used method to determine there is no loss of bone mass [36]. With bone density is dual-energy x-ray den­ the progressive deterioration of ovarian sitometry or DEXA [49, 50]. With the function in the perimenopause, the DEXA method, bone density can be bone destruction starts to predominate measured in the spine, the femoral over bone formation: After the meno- neck and the tibia, and its precision pause, the bone destruction rate rises is approx. 1%. Measurements using faster than the formation rate and the peripheral quantitative computerized calcium balance is negative. The aim tomography (pQCT), on radius or tibia, of every osteoporosis prevention is to are extremely precise, but they do not return the bone metabolism to its pre­ allow an assessment of the spine. Ultra­ menopausal levels, and if possible the sound bone density measurements pro­ bone formation rate should surpass the vide a good screening, but they are not destruction rate again. representative for other bone regions With progressive postmenopause, than the actual scan site. However, the bone density decreases [37, 38] studies investigating the correlation Prophylaxis of Osteoporosis with Estrogens 239 between the peripheral measurement proportion to the duration of hormone sites of the various sonographic meth­ replacement. If we take the mean life ods and the vertebral bone or femoral expectation today into account, osteo­ neck should be available soon. porosis prophylaxis should be continued Like the classical administration of up to an age of about 75. combined estrogen and progestagen, It is still advisable to use the classical pure estrogen replacement therapy in estrogen dosages (Table 2) in the peri­ women after hysterectomy provides menopause and early postmenopause osteoporosis prevention in postmeno­ [50, 62, 63], since it is during this pausal women [51–53]. This beneficial period of life that the treatment of sub­ effect is independent of both the jective complaints such as hot flushes, chronological and the menopausal age. mood changes and sleep disorders is Osteoporosis prophylaxis with estro­ the central issue. However, more recent gens decelerates bone loss in all re­ studies have shown that even lower gions of the skeleton, both in trabecular dosages may be sufficient [45, 52, 64– and in cortical bone [51, 54–56]. It 66]. does not matter whether peroral or Even if osteoporosis prevention is the transdermal (gel, patch) administration only indication, the generally known is chosen for osteoporosis prevention: principles that apply to hormone Both offer an efficient protection [31, replacement therapy (HRT) after the 57]. At our clinic, we compared the menopause should be respected. The protection of bone mass in spine and risk-benefit ratio must be discussed in femoral neck of two of the most com­ detail with every woman. mon administration forms, transdermal and peroral estrogen, whereby both groups received cyclical dydrogeste­ rone. A third group served as a control. PREVENTION IN THE LATER Both peroral (2 mg estradiol) and transdermal estrogen (50 µg estradiol) POSTMENOPAUSE led to a significant increase in bone density within 12 and 24 months. At With increasing time since the meno- the same time, there was a significant pause, there is usually a deceleration of loss of bone mass in the untreated bone turnover. Nonetheless, HRT can control group [58]. These observations correspond with those of various Table 2. Prevention of postmenopausal osteo­ authors who used other progestagens porosis: “Classical” minimum effective estrogen dosages [59] or other forms of administration [51, 57, 58, 60, 61]. Prevention of postmenopausal osteoporosis Even if there are no age limits for the Classical minimum dosages of various induction of hormone replacement, it estrogens used for estrogen-progestagen should be started as early as possible replacement therapy (indication for low­ dose therapy: see text) after the menopause for full benefit, Daily minimum effective estrogen dosages since the greatest bone loss occurs in 1. Peroral administration: the first 3–5 years after the menopause. ● 0.625 mg conjugated equine estrogen Minimum duration of replacement ● 1.6 mg micronized 17β estradiol ● therapy to guarantee osteoporosis pro­ 2 mg estradiol valerate 2. Transdermal (percutaneous) administration: phylaxis is estimated at 5–10 years (see ● 50 µg 17β estradiol below). The fracture risk decreases in 240 Prophylaxis of Osteoporosis with Estrogens also offer reliable protection in the later procedure, which is still not realized postmenopause [30, 51, 58, 67]. On the often enough today. Since there is no other hand, an interruption of replace­ upper age limit for the first prescription ment results in reactivation of the ac­ of hormone replacement therapy, we all celerated bone metabolism, just like have to familiarize ourselves with these before the beginning of replacement problems. New, lower-dosed peroral [68]. This accelerated bone metabolism and transdermal preparation for con­ again leads to a negative bone balance tinuous combined estrogen-progestagen that may be more or less severe depend­ replacement make a major contribution ing on the predisposition, and which towards facilitating replacement therapy ultimately results in postmenopausal for older women. In order to individu­ osteoporosis with an increased inci­ alize the hormone treatment in the later dence of fracture. menopause, the possibility to adminis­ In a comparative study with estrogens ter estrogen locally in the vagina using plus calcium versus calcium mono­ a ring or a deposit ovulum in women therapy, Lindsay et al were able to suffering only from urogenital com­ show in women with a mean time plaints and without any metabolic risk. since the menopause of 12 years that This option is particularly useful in after two-year estrogen treatment the . The fact that it may also be bone density in the lumbar spine and in regarded from the aspect of nursing the femoral neck was significantly care is often overlooked: Especially in higher in the group receiving hormone bedridden women, an atrophic mucosa plus calcium than in the group receiv­ will cause more local discomfort and ing only calcium [30], and that the complaints than a mucosa that is more bone density had actually increased or less eutrophic thanks to local slightly at both sites. Other authors estrogen administration. have also pointed out the importance Whether estrogens and progestagens of calcium supplementation [69–71]. should be administered as osteoporosis More recent data show that bone prevention for women with breast can­ loss could increase again in older cer is currently an issue under discus­ women, mainly in the region of the sion. For more information on this femoral neck [72], which underlines issue, the relevant literature should be the importance of osteoporosis preven­ consulted. According to the valid tion in older and old women. In this recommendations, it seems that the ad­ age group, which usually has the mild­ ministration of estrogens and pro­ est subjective symptoms, mastodynia gestagens to women previously pre­ and other estrogen-induced side effects senting with without often have an extremely negative effect lymphatic or distant metastasis is possi­ on compliance. In older women, good ble under certain conditions. If there clinical results can usually be achieved are no vasomotor complaints, raloxifen with a low-dosed hormone replace­ (see below) or can be ment therapy (1 mg 17-beta estradiol or used. The fact that the anti-estrogen 0.3 mg peroral or also acts as an osteopro­ 25 µg transdermal estradiol) with a tective agent should be considered. Cer­ lower incidence of side effects (see tain progestagens and the synthetic below) [73–77]. steroid tibolone have an osteoprotec­ The older woman in particular needs tive effect, too. In any case, the onco­ our specific advice and an individual logist attending the patient should be Prophylaxis of Osteoporosis with Estrogens 241 consulted before coming to a therapy decision. OSTEOPOROSIS PROPHYLAXIS WITH ESTROGENS AND PROGESTAGENS: HOW LONG? LOW-DOSE THERAPY

If administered long enough, HRT not It is no coincidence that the question of only improves the bone density in post­ whether the classical dosage guidelines menopausal women, but also reduces for the well-known estrogen-progestagen the fracture incidence [7–9]. It has also preparations that are prescribed imme­ been shown that an increased bone diately after the menopause are really loss sets in again as soon as the HRT is optimal in the later postmenopause is withdrawn. Thereby, the bone turnover being raised more and more often. An increases again to roughly the values increasing number of colleagues are found in untreated women after the realizing that those therapeutic regimes menopause [52]. According to other that we are familiar with in the first data, however, the acceleration of years after the menopause are only bone turnover could be slightly lower conditionally suitable for older women. [24]. These varying results are best Especially in older women it is wise to explained by the fact that the extent of start with a relatively low dose because bone loss can vary depending on of the side effects that must otherwise genetic predisposition and nutrition be expected. As more recent studies habits. have shown, such lower dosages are Minimum duration of therapy would usually sufficient for reliable osteo­ appear to be five years or, according to porosis prevention if the calcium intake a different opinion, closer to ten years. is sufficient and there is sufficient Too short administration of HRT in the physical exercise [73–77]. This is con­ first years after the menopause as treat­ firmed both by bone density studies ment for the subjective symptoms does and by controls of the biochemical not guarantee long-term protection bone markers, which were within the against osteoporotic fractures. Cohort normal range. However, when using studies were able to show that long­ such lower dosages the hormone ad­ term prevention reduces the occurrence ministration must be controlled and of spinal deformation in the postmeno­ monitored individually in order not to pause by about 90% [1]. Other data overlook non-responders. Especially, shows that HRT over a period of at least but not only in the older woman it has six years reduces the risk of radius and been shown that a low-dose hormone femoral neck fractures by about half. replacement therapy with 1 mg 17-beta estradiol or 0.3 mg conjugated estrogen peroral or 25 µg estradiol transdermal can achieve satisfactory results with OSTEOPOROSIS PREVENTION: few side effects. The majority of low-dose prepara­ ALTERNATIVES tions available today contain a fixed pro­ gestagen combination, often norethi­ In addition to classical HRT, raloxifen sterone acetate (NETA). (a SERM) or tibolone, both of which 242 Prophylaxis of Osteoporosis with Estrogens have an action similar to that of In younger as in older women, SERMs estradiol, and bisphosphonates [78– lead to normalization of the bone 88] can be used for prevention. turnover and to a certain increase in bone mass [48, 78, 90]. Various other Tibolone studies confirm the beneficial effect of SERMs in osteoporosis prevention. Tibolone has partial estrogenic, pro­ Tamoxifen can also be regarded as a gestagenic and androgenic effects that SERM. Tamoxifen also acts as an estro­ are due to its three main metabolites: gen in the bone, but unlike Tibolone itself may be regarded as a raloxifen it has a stimulating effect on pro-drug. It prevents bone loss and re­ the endometrium. stores an increased bone turnover to the normal range. As we and others have shown, the increase in bone den­ sity during tibolone treatment is signifi­ WHO NEEDS HORMONE cant [58, 77, 89]. In addition, tibolone has a beneficial effect on the classical REPLACEMENT? subjective menopause symptoms, and according to the available data it has a Initially, we can base our decision on favorable effect on the cardiovascular the list of risk factors that increase the system. Tibolone can also be used for likelihood of osteoporosis. Despite all older patients, since it usually leads to efforts to eliminate the risk factors, amenorrhea. about 30–35% of all women remain in the group of patients with a high risk of Selective modulators postmenopausal osteoporosis, presum­ (SERMs) ably on account of their genetic predis­ position. This group is characterized by Various SERMs have been developed pathologically high bone turnover, which in recent years. Today, one preparation can be identified by repeated measure­ from this group is available on the ment of the bone density and the bio­ market: Raloxifen. Raloxifen acts as an chemical bone markers. Since estrogen estrogen antagonist in the breast tissue and endometrium, and as an agonist in Table 3. Requirements on hormonal replacement the bone and in the cardiovascular sys­ therapy with estrogens and progestagens after tem. Available clinical data show that the menopause raloxifen has a beneficial effect on ● Elimination of subjective estrogen deficiency bone density. The breast tissue is not symptoms stimulated, and the endometrium re­ ● Improved quality of life mains atrophic. This action could be of ● Reduction of and mucosa atrophy advantage for women with an in­ ● Prophylaxis/therapy of postmenopausal creased risk of breast cancer. osteoporosis ● Reduction of increased risk for cardiovas­ The disadvantage of raloxifen lies in cular disease the fact that the vasomotor symptoms ● Reduction of increased risk for Alzheimer’s are not improved and may even be disease exacerbated. Therefore, raloxifen is best ● No side effects used for osteoporosis prophylaxis in ● Positive individual risk-benefit ratio ● women without subjective symptoms Good acceptance (long-term replacement!) ● Low price and in older women. Prophylaxis of Osteoporosis with Estrogens 243 deficiency is the main causal factor in ment determines whether they have the group of postmenopausal osteo­ sufficient bone mass or may belong to porosis, these women must be identified the osteoporosis risk group and there­ specifically so that they can benefit fore require hormone replacement. from hormone replacement therapy. However, the following two basic prin­ Since the first publications by Nordin ciples must always be observed: et al [63], Lindsay et al [30, 64] and 1. The bone density that is measured Christiansen et al [52, 65], it has been in one skeletal region does not allow known that estrogen replacement al­ safe conclusions to be drawn with re­ lows the high fracture rate to be reduced gard to the bone density in other skeletal to a normal level. On the other hand, regions and thus a global assessment of senile osteoporosis cannot be prevented the fracture risk, especially where a by hormone replacement alone. As bone of a different skeletal type is con­ shown above, however, the estrogen cerned [22–25]. deficiency can be partly responsible for 2. Osteoporosis is only one of several further bone loss, even at higher ages. indications for hormone replacement We know today that there are no age therapy. The decision for or against limits for starting osteoporosis prophy­ replacement therapy should never be laxis with sexual steroids: A woman can based on the bone status alone. still benefit from hormone replacement therapy that is started ten or more years after the menopause, if she is going through a phase with increased bone PRACTICAL PROCEDURE turnover. It is also accepted that a cer­ tain degree of bone regeneration can be induced with hormone replacement, Of the therapy variants shown in Figure even though it is very limited. Even in 1, cyclical-sequential administration is women with manifest clinical osteo­ mainly used immediately before and porosis, the bone density of the spine after the menopause. The second vari- and the femoral neck can still increase by 2–3% per year, if estrogens and Table 4. Indications for postmenopausal hor­ progestagens are administered in the mone replacement therapy with estrogens and correct dosage [31]. Whilst estrogens progestagens act mainly in the trabecular and less in the cortical bones, it would ● Primary ovarian insufficiency before the age seem that certain progestagens and of 50 ● Existing osteoporosis/reduced bone den­ tibolone also protect the cortical bone sity/pathological biochemical markers [32–34]. ● Neurovegetative dystonia In addition to the indication “preven­ ● Dysphorias/depressive condition tion of osteoporosis”, we should not ● Urogenital atrophy forget all the other classical indications ● Sexual steroid-related disorders of the sexuality for hormone replacement (Table 4). ● High familial risk of osteoporosis Women who are already receiving cor­ ● Cardiovascular prophylaxis in cases with rect estrogen-gestagen replacement for increased personal or familial risk another indication usually do not require ● Muscle, joint and back pain densitometric monitoring of the bone ● Skin atrophy ● density. This is reserved for those cases Atrophy of the mucosa ● Increased risk of Alzheimer’s disease in which the initial bone mass measure­ 244 Prophylaxis of Osteoporosis with Estrogens ant, sequential administration without the result of a reduced peak bone mass interruption of estrogen administration alone, or of deficient estrogen secretion is used mainly within the first 3–5 years after the menopause. Especially in after menopause. However, it is also older patients that do not spend much possible to continue prescribing this time out of doors and have very little regime for older women, if the regular exposure to sunlight, it is important to menstrual bleeding that follows the check whether the minimum 1,25- progestagen phase is accepted, but dihydroxy-vitamin D levels are guaran­ most older women tend to prefer daily teed. In older people, this is commonly concurrent administration of an estro­ not the case [10], so that combined gen and a progestagen, which usually replacement with calcium and vitamin results in amenorrhea. Thereby, the D must be provided. Tillyard et al [62] recurrence of menstrual bleeding is have used the active form of vitamin avoided after the first 3–6 months, D3, calcitriol, with good therapeutic during which irregular bleeding can still success. Normally, however, calcitriol be observed. The patient must however should be reserved for patients with a be informed that unpredictable irregu­ 1,25-hydroxylase deficiency who can­ lar bleeding is common in the begin­ not transform the inactive vitamin D3 ning. contained in their nutrition. It is a mat­ Altogether, there are only few cases ter of course that in addition to any in which peroral administration or hormone replacement a sensible nutri­ transdermal hormone administration is tion and lifestyle that avoids the risk clearly the presentation form of choice factors and includes plenty of physical due to clear medical indications, in exercise is extremely important. A order to either intentionally achieve or balanced diet with sufficient calcium intentionally avoid a first-pass effect. intake, sufficient physical exercise, and Fractures as a consequence of the refraining from excessive smoking or onset of osteoporosis are not always alcohol intake clearly improves the

THERAPY REGIMES ESTROGENS PROGESTAGENS

a) sequential-interrupted 1 21 28/1 21 days

10–12 21 10–12 21 days

b) sequential-uninterrupted

1 12–14 1 12–14 days

c) continuous-combined

Figure 1. Estrogen-progestagen replacement after the menopause: the three basic types Prophylaxis of Osteoporosis with Estrogens 245 chances of preserving a good bone considered that changes in carbohy­ density even in old age. drate metabolism with insulin resist­ Last but not least, the fracture risk is ance are possible around the time of determined not only by the bone mass the menopause, although largely inde­ alone, but also by the tendency to fall, pendent thereof. which can be reduced by specific train­ In a healthy patient, arterial hyper­ ing to improve balance, whereby regu­ tension will not be caused by hormone lar gymnastics up to old age are help­ replacement. In fact, hormone replace­ ful. The fall risk can also be reduced by ment will actually lower the mean avoiding unnecessary sleeping pills pressure slightly. and sedatives, and by checking the Although the metabolic benefits, like homes of elderly people for typical the improvement of subjective climac­ stumbling stones such as loose electri­ teric symptoms, have been acknowl­ cal wiring or folds in carpets. edged by virtually everyone, we known that more than 50% of all women dis­ continue their hormone replacement therapy after one year, and that a maxi­ SIDE EFFECTS AND RISKS mum of 200 out of 1000 patients are still on hormone replacement therapy after 10 years. Since hormone replacement must be The reason for this poor therapy ad­ continued for a period of at least 15–30 herence is probably the unadmitted years in order to be able to achieve the fear of possible side effects and risks. metabolic benefits in the bone and in Even if hormone replacement therapy the cardiovascular system, every woman is regarded as a routine treatment must be aware of the side effects and nowadays, many women still have possible risks of long-term treatment. doubts about the risk-benefit ratio of Most of the side effects are harmless long-term therapy that can only be re­ and usually disappear again if the moved with well-founded and precise administration form or the type of information. In particular, this applies estrogen or progestagen is changed. In to the issue of carcinoma due to HRT, principle, the perfect hormone combi­ an extremely important topic that will nation can be found for every woman. be dealt with in a separate chapter. The weight increase that is frequently feared is about 300 g on average, BIBLIOGRAPHY taking our own data into account. Ba­ sically, it can be put down to rehydra­ 1. Albright F, Smith PH, Richardson AM. Post­ menopausal osteoporosis: Its clinical fea­ tion of the tissue, which is secondary to tures. JAMA 1941; 116: 2465. estrogen administration. A weight gain 2. Seeman E, Hopper JL, Bach LA, Cooper ME, in excess of 800 g is often incorrectly Parkinson E, McKay J, Jerums G. Reduced bone mass in daughters of women with osteo­ attributed to the it­ porosis. New Engl J Med 1989; 320: 554. self, but usually it is independent of 3. Slemenda CW, Christian JC, Williams CJ, exogenous hormones and is due to a Norton JA, Johnston Jr CC. Genetic determi­ nants of bone mass in adult women: a re­ general change in metabolism. It must evaluation of the twin model and the potential be borne in mind that certain pro­ importance of gene interaction on heritabil­ gestagens can stimulate the appetite, so ity estimates. J Bone Miner Res 1991; 6: 561. 4. Theitz G, Buch B, Rizzoli R, Slosman D, that the patient eats more without real­ Clavien H, Sizonko PC, Bonjour JPH. Longi­ izing it. Moreover, it must always be tudinal monitoring of bone mass accumula- 246 Prophylaxis of Osteoporosis with Estrogens

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