Hormonersatztherapie und selektive Östrogenrezeptor-Modulatoren

Zusammenfassung

Eine Hormonsubstitution mit Östrogenen in der Postmenopause - optimale Dosen sind 2 mg Östradiol, 0,625 mg konjugierte equine Östrogene, 1,25 mg Östron, 50 µg Östradiol transdermal - vermag die densitometrisch an frakturrelevanten Regionen quantifizierbare Knochendichte zu erhalten. Die knochenspezifischen Vorteile einer Östrogensubstitution sind unabhängig vom (postmenopausalen) Alter. Die Anwendung eines Gestagens vermindert zumindest nicht diese Effekte. Tibolon, ein Gestagen mit androgenen und östrogenen Partialwirkungen vermag ebenfalls die Knochendichte zu erhalten. Observationsstudien legen nahe, dass eine Östrogensubstitution das Risiko einer Schenkelhalsfraktur um mindestens 25 % reduziert, wenn ein Vergleich zwischen Frauen, die jemals Hormone anwendeten, und denen ohne jegliche gegenwärtige und ehemalige Substitution zugrunde gelegt wird. Die Beendigung einer Substitution zieht nach wenigen Jahren den Wiederanstieg des Frakturrisikos nach sich, die beabsichtigte Osteoprotektion besteht nicht mehr. Es bestehen zur Zeit deutliche Defizite in der Datenlage im Hinblick auf formale Frakturstudien zur Beurteilung der Effektivität einer Substitution, die zur Primärprävention - Verhinderung einer Osteoporose - oder zur Sekundärprävention - Verhinderung weiterer Frakturen - durchgeführt wird. Raloxifen, ein selektiver Östrogenrezeptormodulator, erhält die Knochendichte im Sinn der Primärprävention und vermag die Häufigkeit vertebraler Frakturen bei Frauen mit manifester Osteoporose annähernd zu halbieren. Jede Nutzen-Risiken-Evaluation sollte die erhöhte (erniedrigte) Diagnosewahrscheinlichkeit von Brustkrebs (Kolonkarzinom) bei Langzeitsubstitution mit Östrogenen beinhalten.

Prevention of Osteoporosis - Role of Hormonal Replacement Therapy and Selective Oestrogen Receptor Modulators

Oestrogen replacement therapy (ERT) is generally regarded as first choice for prevention of osteoporosis in women apart from life style modifications. Natural and synthetic oestrogens at least preserve bone mineral density (BMD) dose-dependently irrespective of postmenopausal age and mode of administration. Maximum effects can be achieved by daily use of 2 mg oestradiol, 0.625 mg conjugated equine oestrogens, 1.25 mg oestrone, and 50 µg transdermal patch oestradiol. Progestogens neither attenuate nor augment the effect of oestrogens. Tibolone 2.5 mg daily, a synthetic steroid related to norethisterone acetate, also preserves BMD. Observational studies suggest a hip fracture risk reduction by at least 25 % in permanent non-contraceptive oestrogen users. There are no designated fracture trials available for any oestrogen. A selective oestrogen receptor modulator such as raloxifene reduces vertebral fractures in postmenopausal women with low BMD and incident vertebral fractures, respectively. The recommendation to use oestrogen as first-line pharmacological prevention for postmenopausal osteoporosis is not well supported due to lack of direct evidence by fracture trials and the rare use of oestrogen in (late) postmenopausal women. Fracture trials of women including the advanced should be conducted to overcome the current lack of evidence for ERT compared with other drugs approved for the prophylaxis of postmenopausal osteoporosis. An individual assessment of risks and benefits of long-term HRT including an increased (decreased) likelihood for breast (colon) cancer diagnosis should be taken into account in counselling.

Literatur

• 1 Abdalla H, Hart D M, Lindsay R et al. Prevention of bone loss in postmenopausal women by norethisterone.  Obstet Gynecol. 1985;  66 789-792
• 2 Adachi J D, Srageant E J, Sagle M A et al. A double-blind randomised controlled trial of the effects of medroxyprogesterone acetate on bone density of women taking oestrogen replacement therapy.  Br J Obstet Gynaecol. 1997 ;  104  64-70
• 3 Agnusdei D, Civitelli R, Camporeale A et al. Calcitonin and estrogen.  J Endocrinol Invest. 1990;  13 625-630
• 4 Alexandersen P, Riis B J, Christiansen C. Monofluorophosphate combined with hormone replacement therapy induces a synergistic effect on bone mass by dissociating bone formation and resorption in postmenopausal women: a randomized study.  J Clin Endocrinol Metab. 1999;  84 3013-3020
• 5 Bérard A, Bravo G, Gauthier P. Meta-analysis of the effectiveness of physical activity for the prevention of bone loss in postmenopausal women.  Osteoporos Int. 1997;  7 331-337
• 6 Bjarnason N H, Delmas B H, Mitlak B H et al. Raloxifene maintains favourable effects on bone mineral density, bone turnover, and serum lipids without endometrial stimulation in postmenopausal women. 3-year-study results.  Osteoporos Int. 1998;  8 11
• 7 Castelo-Branco C, Martinez de Osaba M J, Pons F et al. The effect of hormone replacement therapy on postmenopausal bone loss.  Eur J Obstet Gynecol Reprod Biol. 1992 ;  44  131-136
• 8 Castelo-Branco C, Pons F, Gonzalez-Merlo J. Bone mineral density in surgically postmenopausal women receiving hormonal replacement therapy as assessed by dual photon absorptiometry.  Maturitas. 1993;  16 133-137
• 9 Cauley J A, Seeley D G, Ensrud K et al. Estrogen replacement therapy and fractures in older women. Study of Osteoporotic Fracture Research Group.  Ann Int Med. 1995;  122 9-16
• 10 Cheng G J, Liu J L, Zhang Q et al. Prospective double-blind study of CEE and E₂ in peri- and postmenopausal women: effects of bone loss and lipoprotein lipids.   Chin Med J . 1992;  105 929-933
• 11 Christiansen C, Christensen M S, Transbøl I. Bone mass in postmenopausal women after withdrawal of estrogen/gestagen replacement therapy.   Lancet. 1981;  1 459-461
• 12 Christiansen C, Riis B J. 17 β-estradiol and continuous norethisterone: a unique treatment for established osteoporosis in elderly women.  J Clin Endocrinol Metab. 1990;  71 836-841
• 13 Collaborative Group on Hormonal Factors in Breast Cancer . Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer.  Lancet. 1997;  350 1047-1059
• 14 Consensus Development Conference . Prophylaxis and treatment of osteoporosis.  Am J Med. 1991;  90 107-110
• 15 Consensus Development Statement . Who are candidates for prevention and treatment for osteoporosis.  Osteoporos Int. 1997;  7 1-6
• 16 Cummings S R, Browner W S, Bauer D et al. Endogenous hormones and the risk of hip and vertebral fractures among older women.  N Engl J Med. 1998;  339 733-738
• 17 Cummings S R, Eckert S, Krueger K W et al. The effect of raloxifene on risk of breast cancer in postmenopausal women.  JAMA. 1999;  281 2189-2197
• 18 Davis J W, Huster W J, Shen W et al. Estrogen and calcium supplement use among Japanese-American women: effects upon bone loss when used single and in combination.  Bone. 1995;  17 369-376
• 19 Delmas P D, Bjarnason N H, Mitlak B H et al. Effects of raloxifene on bone mineral density, serum cholesterol concentrations, and uterine endometrium in postmenopausal women.  N Engl J Med. 1997;  337 1641-1647
• 20 De Souza M J, Miller B E, Sequenzia L C et al. Bone health is not affected by luteal phase abnormalities and decreased ovarian progesterone production in female runners.  J Clin Endocrinol Metab. 1997;  82 2867-2876
• 21 Devogelaer J P, Lecart C, Dupret P et al. Long-term effects of percutaneous estradiol on bone loss and bone metabolism in postmenopausal hysterectomized women.  Maturitas. 1998;  28 243-249
• 22 Dören M. An assessment of hormone replacement therapy to prevent postmenopausal osteoporosis.  Osteoporos Int. 1999;  2 53-61
• 23 Dören M, Samsioe G. Prevention of postmenopausal osteoporosis with oestrogen replacement therapy and associated compounds: update on clinical trials since 1995.  Human Reprod Update. 2000;  6 419-426
• 24 Dören M, Reuther G, Minne H W et al. Superior compliance and efficacy of continuously combined oral estrogen-progestogen replacement therapy in postmenopausal women.  Am J Obstet Gynecol. 1995;  73 1446-1451
• 25 Eiken P, Kolthoff N, Nielsen S P. Effect of 10 years’ hormone replacement therapy on bone mineral content in postmenopausal women.  Bone. 1996;  19 191-193
• 26 Ettinger B, Genant H K, Cann C E. Postmenopausal bone loss is prevented by treatment with low-dosage estrogen with calcium.  Ann Int Med. 1987;  106 40-45
• 27 Ettinger B, Pressman A, Sklarin P et al. Associations between low levels of serum estradiol, bone density, and fractures among elderly women: the study for osteoporotic fractures.  J Clin Endocrinol Metab. 1998;  83 2239-2243
• 28 Ettinger B, Black D, Mitlak B H et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene.  JAMA. 1999;  282 637-645
• 29 European Consensus Development Conference on Menopause . .  Hum Reprod. 1996;  83 693-700
• 30 Felson D T, Zhang Y, Hannan M T et al. . The effect of postmenopausal estrogen therapy on bone density in elderly women.  N Engl J Med. 1993;  329 1141-1146
• 31 Fisher B, Costantino J O, Wickerham D L et al. Tamoxifen for prevention of breast cancer: report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study.  J Natl Cancer Inst. 1998;  90 1371-1388
• 32 Genant H K, Lucas J, Weiss S T et al. Low-dose esterified estrogen therapy.  Arch Int Med. 1997;  157 2609-2615
• 33 Gilsanz V, Roe T F, Mora S et al. Changes in vertebral bone density in black girls and white girls during childhood and puberty.  N Engl J Med. 1991;  325 1597-1600
• 34 Grady D, Rubin S M, Petitti D B et al. Hormone therapy to prevent disease and prolong life in postmenopausal women.  Ann Int Med. 1992;  117 1016-1037
• 35 Haines C J, Chung T HK, Leung P C et al. Calcium supplementation and bone mineral density in postmenopausal women using estrogen replacement therapy.  Bone. 1995;  16 529-531
• 36 Heikkinen J, Kyllönen E, Kurttila-Matero E et al. HRT and exercise: effects on bone density, muscle strength and lipid metabolism. A placebo controlled 2-year prospective trial on two estrogen-progestin regimens in healthy postmenopausal women.  Maturitas. 1997;  26 139-149
• 37 Henry D, Robertson J, O’Connell D et al. A systematic review of the skeletal effects of estrogen therapy in postmenopausal women. I. An assessment of the quality of randomized trials published between 1977 and 1995.  Climacteric. 1999;  1 92-111
• 38 Hirvonen E, Caccatiore B, Wahlström T et al. Effects of transdermal oestrogen therapy in postmenopausal women: a comparative study of an oestradiol gel and an oestradiol delivering patch.  Br J Obstet Gynaecol. 1997 ;  104  26-31
• 39 Hirvonen E, Lamberg-Allardt C, Lankinen K S et al. Transdermal oestradiol gel in the treatment of the climacterium: a comparison with oral therapy.  Br J Obstet Gynaecol. 1997 ;  104  19-25
• 40 Hulley S, Grady D, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women.  J Am Med Assoc. 1998;  280 605-613
• 41 Itoi H, Minakami H, Sato I et al. Comparison of the long-term effects of oral estriol with the effects of conjugated estrogen, 1 α-hydroxyvitamin D₃ and calcium lactate on vertebral bone loss in early menopausal women.   Maturitas. 1997;  28 11-17
• 42 Joakimsen R M, Magnus J H, Fonnebro V. Physical activity and predisposition for hip fractures: a review.   Osteoporos Int . 1997;  7 503-513
• 43 Kanis J A, Johnell O, Gullberg B et al. Evidence for efficacy of drugs affecting bone metabolism in preventing hip fracture.   Brit Med J. 1992;  305 1124-1128
• 44 Kelley G A. Exercise and regional bone mineral density in postmenopausal women. A meta-analytic review of randomized trials.   Am J Phys Med Rehab . 1998;  77 76-87
• 45 Kohrt W M, Ehsani A A, Birge S J et al. HRT preserves increases in bone mineral density and reductions in body fat after a supervised exercise program.   J Appl Physiol. 1998;  84 1506-1512
• 46 Komulainen M, Kröger H, Tuppurainen M T et al. HRT and vit D in prevention of non-vertebral fractures in postmenopausal women; a 5-year randomized trial.   Maturitas. 1998;  31 45-54
• 47 Komulainen M, Kröger H, Tuppurainen M T et al. Prevention of femoral and lumbar bone loss with hormone replacement therapy and vitamin D₃ in early postmenopausal women: a population-based 5-year randomized trial.   J Clinical Endocrinol Metab . 1999;  84 546-552
• 48 Kristensen H, Ejlertsen B, Dalgaard P et al. Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: a randomized study.   J Clin Oncol . 1994;  12 992-997
• 49 Lindsay R, Hart D M, MacLean A et al. . Bone response to termination of estrogen treatment.   Lancet. 1978;  2 1325-1327
• 50 Lindsay R, Hart D M, MacLean A et al. . Bone loss during oestriol therapy in postmenopausal women.   Maturitas. 1979;  1 279-285
• 51 Lindsay R, Hart D M, Kraszewski A. Prospective double-blind trial of synthetic steroid (Org OD 14) for preventing postmenopausal osteoporosis.   Brit Med J . 1980;  280 1207-1209
• 52 Lindsay R, Tohme J F. Estrogen treatment of patients with established postmenopausal osteoporosis.   Obstet Gynecol . 1990;  76 290-295
• 53 Love R R, Barden H S, Mazess R B et al. . Effect of tamoxifen on lumbar spine bone mineral density in postmenopausal women after 5 years.  Arch Int Med. 1994;  154 2585-2588
• 54 Lufkin E G, Wahner H W, O’Fallon W M et al. . Treatment of postmenopausal osteoporosis with transdermal estrogen.   Ann Inter Med. 1992;  117 1-9
• 55 Maxim P, Ettinger B, Spitalny G M et al. . Fracture protection provided by long-term estrogen treatment.   Osteoporos Int . 1995;  5 23-29
• 56 Meeuwsen I B, Samson M M, Verhaar H J. Evaluation of the applicability of HRT as a preservative of muscle strength in women.   Maturitas. 2000;  36 49-61
• 57 Michaëlsson K, Holmberg L, Mallmin H et al. . Diet and hip fracture risk: results from a case-control study.   Int J Epidemiol . 1995;  24 771-782
• 58 Michaëlsson K, Baron J A, Farahmand B Y et al. Hormone replacement therapy and risk of hip fracture: population based case-control study.   Brit Med J . 1998;  16 1858-1863
• 59 Mosekilde L, Beck-Nielsen H, Sørensen  O et al. Hormonal replacement therapy reduces forearm fracture incidence in recent postmenopausal women - results of the Danish Osteoporosis Prevention Study.  Maturitas. 2000;  36 181-193
• 60 Nachtigall L E, Nachtigall R H, Nachtigall R D et al. . Estrogen replacement therapy 1: a 10-year prospective study in the relationship to osteoporosis.   Obstet Gynecol . 1979;  53 277-281
• 61 Naéssen T, Persson I, Adami H O et al. . Hormone replacement therapy and the risk for first hip fracture.   Ann Int Med . 1990;  113 95-103
• 62 Naéssen T, Berglund L, Ulmsten U. Bone loss in elderly women prevented by ultralow doses of parenteral 17 β-estradiol.   Am J Obstet Gynecol . 1997;  177 115-119
• 63 Naéssen T, Lindemark B M, Larsen H C et al. Better postural balance in elderly women receiving estrogens.   Am J Obstet Gynecol . 1997;  177 412-416
• 64 National Osteoporosis Foundation Status Report . Osteoporosis: Review of the evidence for prevention, diagnosis, and treatment and cost-effectiveness analysis.   Osteoporos Int . 1998;  8 3-88
• 65 Nieves J W, Komar L, Cosman F et al. Calcium potentiates the effect of estrogen and calcitonin on bone mass: review and analysis.  Am J Clin Nutr . 1998;  67 18-24
• 66 Notelovitz M, Martin D, Tesar R et al. Estrogen therapy and variable-resistance weight training increase bone mineral in surgically menopausal women.  J Bone Min Res. 1991;  6 583-590
• 67 Nozaki M, Hashimoto K, Inoue Y et al. Usefulness of estriol for the treatment of bone loss in postmenopausal women.  Nippon Sanka Fujinka Gakkai Zasshi. 1996;  48 83-88
• 68 O’Connell D, Robertson J, Henry D et al. A systematic review of the skeletal effects of estrogen therapy in postmenopausal women. II. An assessment of treatment effects.  Climacteric. 1998;  1 112-123
• 69 Prior J C, Vigna Y M, Schechetr M T et al. Spinal bone loss and ovulatory disturbances.  N Engl J Med. 1990;  323 1221-1227
• 70 Ravn P, Bidstrup M, Wasnich R D et al. Alendronate and estrogen-progestin in the long-term prevention of bone loss: four-year results from the early postmenopausal intervention cohort study. A randomized controlled trial.  Ann Int Med. 1999;  131 935-942
• 71 Recker R R, Davies K M, Dowd R M et al. The effect of low-dose continuous estrogen and progesterone therapy with calcium and vitamin D on bone in elderly women.  Ann Int Med. 1999;  130 897-904
• 72 Reginster J Y, Sarlet N, Deroisy R et al. Minimal levels of serum estradiol prevent postmenopausal bone loss.  Calcif Tissue Int. 1992;  51 340-343
• 73 Resch H, Pietschmann P, Krexner E et al. Effects of one-year hormone replacement therapy on peripheral bone mineral content in patients with osteoporotic spine fractures.  Acta Endocrinol (Copenh). 1990;  123 14-18
• 74 Ribot C, Trémollières F, Pouilles J M et al. Preventive effects of transdermal administration of 17beta estradiol on postmenopausal bone loss: a 2-year prospective study.  Gynecol Endocrinol. 1989;  3 259-268
• 75 Riis B J, Thomsen K, Christiansen C. Does calcium potentiate the effect of estrogen therapy on postmenopausal bone loss?.  Bone Min. 1987;  2 1-9
• 76 Schneider D L, Barrett-Connor E L, Morton D J. Timing of postmenopausal estrogen for optimal bone mineral density.  J Am Med Assoc. 1997;  277 543-547
• 77 Schultz-Zehden B. Frauen-Gesundheit in und nach den Wechseljahren. Die 1000 Frauen-Studie. Gladenbach; Verlag Kempkes 1998
• 78 Speroff L, Rowan J, Symons J et al. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART Study).  J Am Med Assoc. 1996;  276 1397-1403
• 79 Stevenson J C, Cust M P, Gangar K F et al. Effects of transdermal versus oral hormone replacement therapy on bone density in spine and proximal femur in postmenopausal women.  Lancet. 1990;  336 265-269
• 80 Stone K, Bauer D C, Black D M et al. Hormonal predictors of bone loss in elderly women: a prospective study.  J Bone Min Res. 1998;  13 1167-1174
• 81 Studd J WW, McCarthy K, Zamblera D et al. A double-blind, double-dummy, comparative study of Menorest 50® versus Premarin® 0.625 mg in the treatment of menopausal symptoms and the prevention of bone loss in patients with menopausal symptoms.  Clin Drug Invest. 1996;  11 205-213
• 82 . The Writing Group for the PEPI Trial . Effects of hormone therapy on bone mineral density. Results from the Postmenopausal Estrogen/Progestin Interventions (PEPI) trial.  J Am Med Assoc. 1996;  276 1389-1396
• 83 Waller K, Reim S, Fenster L. Bone mass and subtle abnormalities in ovulatory function in healthy women.  J Clin Endocrinol Metab. 1996;  81 663-668
• 84 Ward R L, Morgen G, Dalley D et al. Tamoxifen reduces bone turnover and prevents lumbar spine and femoral bone loss in early postmenopausal women.  Bone Min. 1993;  22 187-194
• 85 Wimalawansa S, Kehely A, Banks L M et al. The effects of percutaneous oestradiol and low dose human calcitonin in postmenopausal bone loss. In: Christiansen C, Johansen JS, Riis BJ (Eds) Osteoporosis 1987. Copenhagen; Osteopress ApS Publishers 1987: 528-532
• 86 Wimalawansa S. Combined therapy with estrogen and etidronate has an additive effect on bone mineral density in the hip and vertebrae: Four-year randomized study.  Am J Med. 1996;  99 36-42
• 87 Winters K M, Adams W C, Meredith C N. Bone density and cyclic ovarian function in trained runners and active controls.  Med Sci Sports Exerc. 1996;  28 776-785