MENOPAUSE ANDROPAUSE Prophylaxis of Osteoporosis with Estrogens 235 PROPHYLAXIS OF OSTEOPOROSIS WITH ESTROGENS M. H. BIRKHÄUSER the later postmenopausal fracture risk INTRODUCTION depends largely on the bone 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 metabolism is estrogen-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 steroids 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 bone density, 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 Europe. 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 calcium 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 estrone and estradiol 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 vitamin D [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 glucocorticoids can be amenorrhea 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 norethisterone acetate (NETA) and mon practice in the United Stated, the gestronol hexanoate, actually have their administration of estrogen alone with­ own osteoprotective activity [30–32], out gestagen in women with an intact whilst medroxyprogesterone 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: ● Tibolone 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 ● Transdermal (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